WO2012010832A1

WO2012010832A1 - Injection device

Info

Publication number: WO2012010832A1
Application number: PCT/GB2011/001082
Authority: WO
Inventors: Kevin Stamp
Original assignee: Future Injection Technologies Limited
Priority date: 2010-07-20
Filing date: 2011-07-19
Publication date: 2012-01-26
Also published as: GB201012179D0; GB201112465D0; GB2482241A

Abstract

An injection device is disclosed, the device having a proximal end and a distal end, wherein the distal end is located closest to an injection site In use, the device comprising: a container; a septum sealing a distal end of the container; and a needle located distal to the container; wherein the container comprises a first chamber including a first component and a second chamber including a second component, the first and second chambers being initially separated from one another by a seal to prevent mixing of the first and second components, wherein the device is arranged on activation to provide a septum piercing stage and then a mixing stage; and wherein the septum piercing stage is a stage in which the needle is caused to pierce the septum to place the needle in fluid communication with the interior of the container, and the mixing stage is a stage in which the seal between the first and second chambers is breached to permit fluid communication between the first and second chambers to allow the first and second components to mix thereby providing a composition comprising the first and second components for injection. A transition between the septum piercing stage and the mixing stage is controlled by the rotational movement of a part of the device.

Description

Injection Device

The present invention relates to injection devices, or more particularly but not exclusively to automatic injection devices (so called "autoinjectors").

There is increasingly a need for injection devices in which some or all of the steps required to inject a dose of a composition may proceed automatically once the device is activated by a user. Automatic injection devices are desirable in that they may allow a user to self administer medication, e.g. in the home, reducing the reliance upon healthcare

professionals. This may be useful in the treatment of long term or chronic conditions such as diabetes or arthritis, resulting in more effective use of resources and greater convenience to the patient. By automating some or all of the steps involved in injecting a dose of a substance, the scope for user error may be reduced, providing greater reliability and more effective treatment.

Various devices have been proposed which may automatically perform an injection cycle including the steps of advancing a needle for insertion, dispensing a liquid through the needle and then retracting the needle. It is desirable that the devices are pre-filled with the composition to be dispensed before being supplied to a user. This may provide greater confidence that the correct composition and dose is delivered when the device is operated, and may ensure that sterility is maintained. To this end, automatic injection devices often include a syringe pre-filled with the liquid to be dispensed.

If a composition to be dispensed is to be pre-filled into a part of the device during manufacture, the composition may have to withstand potentially varied environmental conditions e.g. heat, humidity during assembly, packaging, transport, storage etc before being supplied to a user. In practice it is not possible to accurately control the conditions under which the device is maintained subsequent to filling and before use. The device may not be used immediately by the user. For example a user may be supplied with several months' supply of single use devices. Although some compositions are able to maintain their properties reliably until used, the incorporation of other compositions into pre-filled injection devices has presented greater difficulties.

Certain drugs do not have a shelf life which would enable them to be pre-filled into an injection device. The active components of some drugs may interact with one another, the environment, or with their surrounding container in a detrimental manner. Some compositions are not stable in their liquid form. These issues are commonly encountered in the context of newer "bio" type drugs, although may be applicable to a range of different drugs. In many cases such compositions must be prepared just prior to injection. Conventionally, before injecting a dose of such liquids which are unsuitable for pre-filling into a device for injection, a user would have to mix certain components together in order to create a dose of the liquid to be injected immediately prior to injection. This would involve a series of operations often including multiple vials and needles. The reliance upon the user to carry out such steps introduced considerable risk of user error in terms of the identity and quantity of each component to be used, and compromised sterility.

Recently a technique known as "lyophilization" has increasingly been used to impart greater stability, longer shelf life and broader temperature tolerance to pharmaceutical compositions which are unstable in aqueous solution. This process involves freeze drying of a product to create a lyophilized substance with greater stability. This lyophilized substance must then be reconstituted prior to use by mixing it with a solvent. Lyophilized drugs find

considerable application in the treatment of conditions which would ideally be treated using self administration of the drug e.g. in the home. The need for reconstituting the drug has, however, until now present difficulty in achieving this.

A cartridge has been proposed which may eliminate the need for the user to use multiple vials and/or needles to mix components together, allowing mixing of multiple components to be carried out in a single operation when the user depresses a plunger. These cartridges may be used in conjunction with lyophilized/solvent drugs, liquid/liquid drugs or powder/liquid drugs. Such cartridges are known as "Vetter" cartridges. The cartridge includes a glass body with a stopper at either end, and front and rear chambers between the ends separated by an intermediate piston. A rear piston is associated with the rear stopper. Initially the two components to be mixed are located respectively in the front and rear chambers and are prevented from mixing by the intermediate piston. A liquid component is located in the rear chamber. .The user may then advance the rear stopper via a plunger engaging the rear piston to move it axially toward the front end of the cartridge. As the liquid in the rear chamber is relatively incompressible, movement of the rear piston forward will cause the intermediate piston to advance under the action of the liquid. This may bring the intermediate piston into alignment with a bypass channel in the cartridge body placing the front and rear chambers into fluid communication with one another. The liquid in the rear chamber may then flow into the front chamber to mix with the component therein, thus providing a mixed liquid component ready for injection.

While dual chamber cartridges of this type may solve some of the problems associated with mixing dual component compositions for injection, the user is still required to carry out certain operations manually, which may introduce error and reduce sterility. Mixing of the drug is only one of many stages required to appropriately administer an injection. For example, the user must join the cartridge to a needle. The timing and manner in which this is done may affect the efficacy of the liquid to be injected, as well as causing potential anxiety to a user. Some users may be unable to easily perform such steps e.g. due to manual impairment. The user must then manually perform an injection cycle involving needle advancement, dispensing and needle retraction.

Accordingly, the Applicant has realised that there remains a need for improved automatic injection devices for use in conjunction with compositions which are produced by mixing multiple components together prior to injection.

In accordance with a first aspect of the present invention there is provided;

an injection device;

the device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use;

the device comprising;

a container;

a septum sealing a distal end of the container;

and a needle located distal to the container;

wherein the container comprises a first chamber including a first component

and a second chamber including a second component, the first and second chambers being initially separated from one another by a seal to prevent mixing of the first and second components,

wherein the device is arranged on activation to provide a septum piercing stage and then a mixing stage;

wherein the septum piercing stage is a stage in which the needle is caused to pierce the septum to place the needle in fluid communication with the interior of the container, and the mixing stage is a stage in which the seal between the first and second chambers is breached to permit fluid communication between the first and second chambers to allow the first and second components to mix thereby providing a composition comprising the first and second

components for injection;

wherein a transition between the septum piercing stage and the mixing stage is controlled by the rotational movement of a part of the device.

Accordingly, the present invention provides an injection device in which separate stages of piercing of the septum and mixing of components to provide a composition for injection are provided once the device is actuated. A transition between the stages is controlled by the rotation of a part of the device ("the rotating part"). The transition occurs automatically as a result of the rotational movement, and thus, in contrast to prior art arrangements, the user is not required to carry out the specific actions required to perform either the septum piercing or mixing steps manually. For example, both stages may occur sequentially as the user carries out a single action, such as causing an actuator to enter a housing of the device. The user does not need to handle multiple needles, vials etc. As the device relies upon a mechanical arrangement to provide the transition between the stages, the need to use electronic processors is avoided.

The septum piercing stage places the needle in fluid communication with the interior of the container. This permits gas to vent from the interior of the container through the needle during the subsequent mixing stage. The septum piercing stage also places the needle in a condition ready for providing an injection when the mixing stage is complete, such that the composition formed by mixing of the first and second components may pass through the needle into the injection site. During the septum piercing stage the needle is secured to the container such that it may subsequently move with the container. Thus the septum piercing stage involves piercing the septum to place the needle in fluid communication with the interior of the container and to secure the needle to the container.

The invention provides a device in which the septum piercing stage and the mixing stage are distinct from one another. Thus the mixing stage does not commence until the septum piercing stage is complete. This is advantageous as by piercing the septum at the distal end of the container before the components of the container are mixed, gas e.g. air present in the container may be vented throughout the mixing stage. This may reduce the risk of gas being injected into the body with the composition injected in use.

The septum piercing stage may be achieved in any suitable manner. In embodiments of the invention the septum piercing stage comprises a step of mutually compressing the container and needle in the axial direction to cause the needle to pierce the septum. Thus during the septum piercing stage the combined length of the needle and container is reduced to cause the needle to be pushed on to the container thereby piercing the septum. The axial compression step may involve movement of the needle and/or the container.

In embodiments only one of the container and needle moves in the axial direction during the septum piercing stage. In some embodiments the container may be maintained in a fixed axial position as the needle is moved toward the container to cause the needle to pierce the septum, or in other embodiments the needle may be maintained in a fixed axial position as the container is moved toward the needle to cause the needle to pierce the septum.

During the septum piercing stage, regardless of the manner in which it is carried out, in some sets of embodiments the needle is retained in a fixed axial position relative to a distal end of the device and the device is arranged such that the container and the distal end of the device are caused to move axially relative to one another to cause the needle to pierce the septum. The needle may be retained in a fixed axial position relative to a distal end of a housing of the device e.g. a distal end thereof.

It is desirable to retain the needle against axial movement relative to a distal end of the device during the septum piercing stage to facilitate this operation. The distal end of the device and the container may then be moved relative to one another to result in axial compression of the needle and container in order to cause piercing of the septum. In some sets of embodiments, the device comprises a needle retaining arrangement for retaining the needle in a fixed axial position relative to a distal end of the device during the septum piercing stage, and optionally the mixing stage. The needle retaining arrangement may retain the needle in a fixed axial position relative to the distal end of the device during axial compression of the container and the needle, for example as the container is moved axially in the distal direction relative to the needle to cause the needle to pierce the septum. The retaining arrangement may also retain the needle in a fixed rotational position. In some embodiments the device comprises a housing and a distal part of the housing comprises the needle retaining arrangement. In some sets of embodiments the distal part of the housing defines a distal end which is intended to be located against the skin during delivery of an injection. The needle retaining arrangement may be located radially outwardly of the needle.

It is desirable that the needle is also retained in a fixed axial position relative to the distal end of the device during the mixing stage. Once the septum piercing stage is complete the needle has been secured to the container. Thus, retaining of the needle in a fixed axial position relative to the distal end of the device will retain the container in a fixed axial position relative to the distal end of the device as the mixing stage proceeds, facilitating e.g. advancing of a piston within the container. It will be appreciated that the needle is therefore preferably retained in a fixed axial position relative to the distal end of the device during the septum piercing stage and the mixing stage, and in embodiments, the device comprises a needle retaining arrangement, and the needle retaining arrangement is arranged to retain the needle in a fixed axial position relative to the distal end of the device in the septum piercing and mixing stages.

The needle retaining arrangement may be configured to retain the needle in a fixed position in any suitable manner. The retaining arrangement retains the needle in a fixed position relative to the retaining arrangement. The retaining arrangement may comprise one or more parts. The retaining arrangement may cooperate directly or indirectly with the needle to retain the needle in a fixed axial position during the septum piercing stage, and preferably the mixing stage.

It will be appreciated that the proximal or rear end of the needle will pierce the septum of the container in the septum piercing stage. The needle may comprise a proximal or rear end which pierces the septum and a distal or front end through which the composition to be dispensed passes to enter an injection site in use. The needle may therefore be a double pointed needle. The needle may comprise a single integral needle having proximal and distal points or may comprise proximal and distal needles in fluid communication with one another.

In accordance with some sets of embodiments the needle is part of a needle assembly, and the device thus comprises a needle assembly comprising the needle. ln these embodiments the needle assembly may comprise a needle holder. The needle holder holds the needle in a fixed position relative to the needle holder.

The needle assembly may comprise a needle shield. The needle shield covers a distal end of the needle. This may guard against accidental needle stick injuries and may also maintain sterility of the needle.

The needle assembly may further comprise a seal sealing a proximal end of the needle assembly. In embodiments the seal is located between the septum and the proximal end of the needle. The seal is advantageously arranged to be breached by the proximal end of the needle during the septum piercing stage. The seal may be any suitable membrane e.g. a paper membrane. It has been found that the act of mutually compressing the needle and the container to cause the needle to pierce the septum may also breach a seal located between the needle and the septum. However, in some embodiments a seal severing arrangement, such as a blade, may be located between the distal end of the container and the proximal end of the needle assembly to facilitate breaching e.g. rupturing of the seal.

The needle assembly may comprise any or all of the above components. A needle assembly may advantageously be provided as a unit including a needle, needle holder, needle shield and a proximal seal. The needle assembly may be an off the shelf needle assembly used without modification. Such sterile pre-pack units are readily available.

In embodiments comprising a needle assembly and a needle retaining arrangement, the needle retaining arrangement may cooperate with a part of the needle assembly to retain the needle in a fixed axial position relative to a distal end of the device. Preferably, the needle is releasably retained by the needle retaining arrangement in the fixed axial position. The needle retaining arrangement may then cooperate with a part of the needle assembly other than the needle. The needle retaining arrangement may be located radially outwardly of the needle assembly. In these embodiments the needle should be held in a fixed axial position within the needle assembly with respect to the part with which the needle retaining arrangement cooperates. The part of the needle assembly with which the retaining arrangement cooperates may be a needle shield.

In these embodiments in which the needle retaining arrangement cooperates with a part of the needle assembly, the part of the needle assembly and the needle retaining arrangement may comprise respective formations which cooperate to retain the needle in a fixed axial position relative to the distal end of the device. In embodiments the part of the needle assembly comprises a flange with which the retaining arrangement cooperates. The flange may be a collar.

The needle retaining arrangement may comprise one or more retaining members for retaining the needle. In embodiments having a needle assembly, the retaining members may cooperate with a part of the needle assembly. In some sets of embodiments the needle retaining arrangement comprises a plurality of needle retaining members which cooperate with a flange of a needle shield of a needle assembly.

In some sets of embodiments the retaining arrangement may be arranged to resiliently clamp around a part of the needle assembly, and may comprise one or more retaining members arranged to resiliently clamp against a part of the needle assembly. However, it will be appreciated that any suitable arrangement may be used to retain the needle, for example cooperating lugs and slots etc. Whether or not they are arranged to clamp around the needle assembly, the retaining members may comprise hooks for engaging a part of the needle assembly. In embodiments the retaining members comprise hooks arranged to engage distally of a cooperating formation of the part of the needle assembly to inhibit axial movement of the needle toward the distal end of the device.

The needle is initially retracted relative to the distal end of the device. It will be appreciated that subsequently during an injection cycle the needle must be advanced relative to the distal end of the device for insertion into the skin. Thus in embodiments the needle retaining arrangement is arranged to releasably retain the needle in a fixed axial position relative to the distal end of the device. The needle retaining arrangement may be released to permit axial movement of the needle relative to the distal end of the device. In this way the needle may be held securely while the container is pushed onto the proximal end thereof in the septum piercing stage, and preferably the mixing stage, but may be free to advance axially relative to the distal end during an injection cycle after mixing has occurred. In embodiments the needle retaining arrangement is arranged to be releasable to permit axial movement of the needle only in a direction toward the distal end of the device. For example a part of the needle retaining arrangement inhibiting movement of the needle toward the distal end of the device may be releasable but not a part inhibiting movement of the needle toward a proximal end of the device.

In some sets of embodiments the device may comprise a blocking arrangement blocking the release of the needle retaining arrangement which must be displaced to release the needle retaining arrangement. In some embodiments the blocking arrangement must be rotated to release the needle retaining arrangement. In some embodiments in which the needle retaining arrangement comprises a plurality of retaining members, displacement of the blocking arrangement may allow the retaining members to move radially outwardly to release the needle. In some embodiments the blocking arrangement may comprise one or more circumferentially extending slots which may be moved into rotational alignment with the retaining members.

In some sets of embodiments the needle retaining arrangement is arranged such that it may only be released upon manual intervention. For example, in embodiments comprising a blocking arrangement the blocking arrangement is arranged such that it must be released manually. The needle retaining arrangement may be arranged such that it may not be released until the septum piercing stage is complete, and preferably not until the mixing stage is complete. This may be achieved in any manner.

In embodiments the septum piercing stage and the mixing stage are linked to a relative travel of an actuator of the device. The needle retaining arrangement may be releasable only after an actuator of the device has moved a given relative distance required to perform the septum piercing stage and preferably also the mixing stage. The movement of the actuator may automatically release the retaining arrangement, or may permit the user to carry out a releasing step. The device may be located in a package which blocks release of the needle retaining arrangement until the septum piercing stage and optionally the mixing stage is complete. The package may selectively block the release of the needle retaining arrangement depending upon the relative position of an actuator of the device, e.g. blocking the release until the actuator has travelled a given relative distance. For example the packaging may be removable once the septum piercing and preferably also the mixing stages are complete to unblock the release of the needle retaining arrangement or to permit its release e.g. by removal of a component etc.

In some embodiments in which the device comprises a needle assembly having the needle, the needle retaining arrangement is arranged to cooperate with a removable part of the needle assembly. The removable part may be a component which is removable only after the septum piercing stage, and in embodiments after the mixing stage is complete. In embodiments having a needle assembly, the retaining arrangement may cooperate with a removable needle shield of the needle assembly to maintain the needle in a fixed axial position relative to the distal end of the device. In embodiments release of the needle retaining arrangement may permit the removal of the removable component.

In some sets of embodiments the device comprises a guard which must be displaced by a user before delivery of an injection. The guard may need to be moved from an initial position or may need to be removed completely from the device before delivery of an injection. In some embodiments the guard must be rotated or squeezed, and in embodiments additionally moved axially from an initial position to permit delivery of an injection. In embodiments the guard may comprise the blocking arrangement for blocking release of the needle retaining arrangement. Displacement of the guard may then release the needle retaining arrangement. In

embodiments the displacement of the guard causes the needle shield to be dislodged to allow it to be removed from the device. In some embodiments removal of the guard from the device results in removal of the needle shield.

In accordance with the invention in any of its embodiments, the container may be of any suitable form. In some sets of embodiments the container is a cartridge. It will be appreciated that the container is pre-filled with the first and second components. This avoids the need for the user to carry out any operations using vials, multiple needles, transfer devices etc providing greater ease of use and helping to maintain sterility. The container is pre-filled during assembly. The container may be pre-filled prior to or as part of assembly of the device as a whole. The container may be supplied as a sterile package which may be incorporated in the device during assembly. The device of the present invention may advantageously utilise a standard "off the shelf cartridge without modification. One suitable container is a dual container cartridge produced by Vetter Pharma International. Such cartridges are commonly referred to as "Vetter" cartridges.

The container comprises a container body. The container body may be barrel shaped. The container body may be a glass body. The container may define a front shoulder.

The container is sealed at the distal end by a septum. The septum may be any suitable rupturable membrane. In embodiments the container comprises a distal stopper having said septum. The proximal end of the container should be sealed to maintain sterility of the content of the container.

In accordance with any of the embodiments of the invention the container may comprise a proximal slidable wall e.g. piston sealing the proximal end thereof. The slidable wall may be moved to discharge the content of the container during delivery of an injection. The pistons of the container may be of any suitable material e.g. rubber. The container may additionally comprise a proximal stopper distally of the proximal slidable wall, and movable with the wall in use.

In preferred embodiments the first chamber is a proximal chamber and the second chamber is a distal chamber. Thus in these embodiments the first and second chambers lie one behind the other. The distal end of container and device may also be referred to as the front end, being closest to the injection site in use. The volume of the first and second chambers may be the same or different. In some embodiments each chamber has a volume in the range of from 0.1 ml to 10.0 ml, or from 0.5 ml-5.0 ml, or from 0.5 ml to 1.5 ml. The volume of the chambers is the initial volume prior to actuation of the device. In some sets of

embodiments the container is a dual chamber container having only first and second chambers.

In some sets of embodiments the seal separating the first and second chambers is a slidable wall, e.g. a piston. The seal initially prevents fluid communication between the first and second chambers to prevent mixing of the first and second components.

In accordance with the invention, the seal between the first and second chambers may be breached in any suitable manner during the mixing stage to allow fluid communication between the front and rear chambers, and permit the content of the first and second chambers to mix and provide the composition for injection. For example, it could be envisaged that this step may involve rupturing of the barrier. However, in preferred embodiments, the step of breaching the seal comprises displacing the seal, preferably axially, to allow the first and second components to mix, and the device is configured to carry out such a step. In embodiments the device is arranged such that during the mixing stage a proximal slidable wall of the container is advanced axially within the container to cause displacement of the seal. This may be achieved in embodiments using an actuator which engages a proximal slidable wall of the container. An axial force applied to the proximal slidable wall may be transmitted to the seal via the first component, e.g. a relatively incompressible liquid, such that axial movement of the proximal slidable wall may cause the seal to advance. In embodiments, as the first component enters the second chamber the proximal slidable seal may move closer to the seal and after mixing is complete may contact the seal.

In some sets of embodiments the container comprises a bypass channel connecting the first and second chambers, which bypass channel is initially blocked by the seal to prevent mixing of the first and second components. The step of breaching the seal then may comprise displacing the seal to unblock the channel to allow fluid to flow through the channel between the first and second chambers allowing the first and second components to mix.

The first and second components may be of any suitable type which may be mixed to provide a composition for injection. The composition for injection is a liquid composition. In embodiments at least one of the first and second components is a liquid, preferably an aqueous liquid. Preferably the first component is a liquid. The other component may be a solid or a liquid. In preferred embodiments the first component is a liquid and the second component is a solid. When the component is a solid component it may be in the form of a powder. In preferred embodiments the first component is a solvent and the second component is a lyophilized drug. It will be appreciated that the first and second components are mixed to provide a composition which is different to the first and second components. When the component in the proximal chamber is a liquid, the relatively incompressible liquid may transmit an axial force applied to a proximal slidable wall of the container to the seal to cause the seal to be displaced axially as the proximal slidable wall is advanced axially. The use of a first component which is a liquid also enables the first component to flow via a bypass channel into the second chamber when the seal is breached in embodiments having such a channel.

In some sets of embodiments the device comprises a container housing within which the container is disposed. The container housing may protect the container during operation of the device, and may comprise formations which cooperate with other parts of the device to enable the various stages in operation to proceed. The container may be immobilised in the housing.

In accordance with the invention, the transition between the septum piercing and mixing stages is controlled by a change in the rotational position of a part of the device. In some sets of embodiments the part is movable from a first rotational position to a second rotational position at which the transition between the septum piercing and mixing stages occurs. The first and second rotational positions may be separated from one another by any amount. In embodiments the first and second rotational positions are separated from one another by an angle of less than 60 degrees, or less than 40 degrees. The first and second rotational positions may be separated from one another by at least 20 degrees.

The rotation of the rotational pari enables the mixing stage to occur. In some sets of embodiments the mixing stage may only commence when the part has reached the second rotational position. The septum piercing stage takes place before the part reaches the second rotational position. In some sets of embodiments the device is configured such that the septum piercing stage occurs as the part rotates toward the second rotational position. The septum piercing stage may continue until the part has moved from the first rotational position to the second rotational position at which point the mixing stage commences.

In accordance with the invention, once the device is actuated the rotating part is caused to move from the first rotational position to the second rotational position providing the transition between the septum piercing and mixing stages. Accordingly the device comprises an arrangement for driving the part from a first rotational position to a second rotational position.

In some sets of embodiments the device comprises an actuator movable axially relative to a distal end of the device, and the rotation of the rotating part occurs as a result of the relative axial movement of the actuator. The rotation may occur as a result of the relative axial movement of the actuator toward the distal end of the device. The actuator may be an actuating rod. It will be appreciated that the actuator may be formed from more than one section joined together, although in other embodiments the actuator is a single piece actuator.

The actuator might be driven axially by an automatic arrangement, e.g. by means of driving means such as a spring or compressed gas. However, in preferred embodiments the actuator is arranged to be manually driven. Thus, in embodiments the actuator is moved manually relative to the distal end of the device e.g. by a user.

These arrangements having an actuator which is operated manually are advantageous in that they are similar to the manner in which conventional devices operate, in which the user is required to depress an actuating rod e.g. plunger in order to cause components in a dual chamber cartridge to be mixed, although in such arrangements the septum piercing stage must be carried out using a separate operation by a user. The use of a similar user operation may provide greater familiarity and ease of understanding to the user.

In some sets of embodiments the relative axial movement of the actuator is provided by the mutual axial compression of the actuator and another part of the device. The other part of the device may be a housing e.g. a proximal housing . It will be appreciated that there may not necessarily be axial compression of the device as a whole, for example the mutual axial compression of the parts may occur within a housing of the device. The mutual axial compression results in a reduction in a combined length of the actuator and the other part.

In some embodiments the device comprises a housing, and the actuator projects from a proximal end of the housing. In these embodiments the actuator may move into the housing as it moves axially relative to the distal end of the device. The movement of the actuator into the housing may cause the rotation of the rotating part of the device. In these embodiments there is a mutual axial compression of the actuator and the housing.

It will be appreciated that references to the axial movement of the actuator refer to the axial movement of the actuator relative to a distal end of the device, and this may be achieved by movement of the actuator while keeping the distal end of the device in a fixed axial position, or by keeping the actuator in a fixed axial position and moving the distal end of the device in relation thereto. In either case there may be a mutual axial compression of the actuator and another part of the device. For example, in embodiments, a housing of the device may be grasped by a user as the actuator is moved relative to the distal end of the device, e.g. into the housing. In some arrangements the user may cause the actuator to move relative to the distal end of the device by urging the proximal end of the housing toward the proximal end of the actuator. For example the user may invert the device and press the proximal end of the actuator against a surface while grasping the housing and urging the housing toward the proximal end of the actuator in use. By locating the device in an inverted position in this way while causing the actuator to move relative to the distal end of the device, air may vent through the distal end of the needle more readily during the mixing stage. The device could of course be used in a non inverted position, with the user pressing down on the proximal end of the actuator to cause it to move relative to the distal end of the device and e.g. move into the proximal end of the housing.

In accordance with the invention in any of its embodiments, the actuator could be arranged to rotate as it moves axially relative to the distal end of the device, such that the rotating part could be a part of the actuator, e.g. a distal end of the actuator. However, it is preferable that the actuator does not rotate. In preferred embodiments the actuator does not rotate as it moves axially, and may be arranged to be incapable of rotation. In embodiments the device comprises means for constraining the actuator against rotational movement as it moves axially. The constraining means and the actuator may comprise respective formations which cooperate to maintain a given rotational alignment of the actuator as it moves axially. For example cooperating sets of lugs and slots, hooks and grooves etc may be used. In some embodiments the actuator comprises one or more axially extending tracks each of which cooperates with one or more respective lugs to inhibit rotational movement of the actuator. In some embodiments the device comprises an annular member through which the actuator slides. The annular member may then comprise the constraining means which cooperates with a formation of the actuator.

In some sets of embodiments the relative axial movement of the actuator causes the rotating part of the device to rotate relative to the actuator. Thus in these embodiments the rotating part is separate from the actuator. The actuator may cause the rotating part to rotate directly or indirectly via an intermediate arrangement. In some embodiments the actuator, preferably a distal end thereof, directly engages the rotating part.

In embodiments in which the rotation of the rotating part of the device is caused as a result of relative axial movement of the actuator, e.g. by the mutual axial compression of the actuator and another part of the device, movement of the actuator at least causes the transition between the septum piercing and mixing stages to occur. However, in preferred embodiments the relative axial movement of the actuator is also required in order that the septum piercing and mixing stages may proceed. Thus the septum piercing and mixing stages may be linked to the relative axial travel of the actuator. In embodiments the septum piercing and mixing stages occur under the action of the actuator as the actuator moves axially relative to the distal end of the device e.g. toward the distal end. In embodiments the septum piercing stage and then the mixing stage occur in sequence under the influence of the actuator as the actuator travels relatively in an axial direction from an initial position toward a distal end of the device. In embodiments the septum piercing and the mixing stages may occur as the actuator is caused to travel axially relative to the distal end of the device under the action of a manually applied driving force.

In this way the septum piercing stage and the mixing stage may be achieved under the action of a single axial movement of the actuator relative to the distal end of the device. In some embodiments, a user may grasp the housing and urge it toward the proximal end of the actuator with both the septum piercing and mixing stages occurring as the actuator moves relative to the distal end of the device.

In embodiments the septum piercing stage occurs as the actuator travels over a first axial distance relative to the distal end of the device and the mixing stage is occurs as the actuator is moved over a second axial distance relative to the distal end of the device. The first and second axial distances may be preset distances. The septum piercing stage may commence once the actuator starts to move, and this may be before or as the rotating part starts to rotate under the influence of the axial movement of the actuator.

In some sets of embodiments the septum piercing and mixing stages may occur one after the other under the influence of the actuator as the actuator and a part of the device are mutually axially compressed. In embodiments in which the actuator moves into a proximal part of a housing of the device as it moves axially relative to the distal end of the device, the septum piercing and mixing stages may occur one after the other under the influence of the actuator as the actuator and the housing are mutually axially compressed.

In some sets of embodiments mutual axial compression of the container and needle occurs under the influence of the actuator during the septum piercing stage. This may result in the septum being pushed on to the rear end of the needle. In embodiments the device is arranged such that an axial force is transmitted between the actuator e.g. a distal end thereof, and a proximal end of the container during the septum piercing stage. In this manner movement of the actuator relative to the distal end of the device may cause the container to advance relative to the distal end of the device. In accordance with any of the embodiments of the invention the device may be arranged such that the actuator e.g. a distal end thereof, may not move axially relative to the container during the septum piercing stage. Thus in some sets of embodiments the first position of the rotating part is a position in which the actuator is not able to move axially relative to the container.

The actuator may advance the container in any manner, directly or indirectly. In embodiments in which the container is provided in a container housing, the actuator e.g. a distal end thereof may engage a part of the container housing e.g. a proximal end thereof.

The device may comprise means for limiting the axial movement of the container relative to the needle during the septum piercing stage. For example a part of the container may be arranged to abut a part of a needle assembly comprising the needle to limit axial movement of the container relative to the needle. For example a distal stopper of the container may abut a proximal end of a needle holder. A transition to the mixing stage may be arranged to coincide with this point.

In embodiments the device is arranged such that the actuator moves axially relative to the container during the mixing stage. Accordingly in embodiments the rotating part rotates to a second position which permits the actuator to move axially relative to the container.

In embodiments the actuator is arranged to cause a slidable wall at the proximal end of the container to advance within the container in order to breach the seal between the first and second chambers during the mixing stage. In embodiments rotation of the rotating part enables a distal end of the actuator to advance a proximal slidable wall of the container relative to the distal end of the container. The rotation of the rotating part enables the actuator to start to move the proximal slidable wall relative to the distal end of the container. In the septum piercing stage the distal end of the actuator may not advance the proximal slidable wall relative to the distal end of the container.

In embodiments advancement of the proximal slidable wall under the influence of the actuator causes the seal between the first and second chambers to be displaced to permit fluid communication between the first and second chambers. As discussed above, the seal may be displaced to unblock a bypass channel connecting the first and second chambers. In embodiments in which the first component is a liquid, the axial force exerted by the actuator upon the proximal slidable wall is transmitted to the seal via the first component located between the slidable wall and the seal.

The actuator may cause the slidable wall to advance directly or indirectly. For example the actuator, or a distal end thereof, may drive an intermediate part e.g. a plunger axially into the container. In other embodiments a distal end of the actuator is arranged to advance axially - ^]5 - within the container relative to the distal end of the container for advancing the proximal slidable wall. The distal end of the actuator may then directly engage the proximal wall of the container.

In accordance with the invention in any of its embodiments the rotating part may be any suitable part. In embodiments having an actuator, the rotating part may be arranged to transmit an axial force between an actuator and the container during the septum piercing stage. In embodiments the rotating part may be located between a distal end of the actuator and the proximal end of the container.

In some sets of embodiments the device comprises a container housing within which the container is disposed, and the rotating part is provided by a proximal part of the container housing. In embodiments the container housing rotates with the rotating part. The part may be a separate part joined to a main body of the housing, or may be integrally formed with a main body of the housing. In these embodiments the container housing may immobilise the container. _ Thus the container may also rotate. It will be appreciated that in embodiments in which a container housing rotates, the container itself will rotate during the septum piercing stage. This may help to twist the needle onto the container.

In embodiments of the invention the device is arranged such that the rotating part moves axially relative to a distal end of the device as it rotates. Preferably, this occurs during the septum piercing stage. In embodiments in which the rotating part is caused to rotate by an actuator, the rotating part may also move axially under the influence of the actuator. In embodiments the rotating part does not move axially during the mixing stage. In embodiments comprising a needle assembly a part of the needle assembly may provide a forward stop preventing further advancement of the rotating part in the axial direction. For example, in embodiments a container housing comprising the rotating part rotates until the actuator is able to move axially relative thereto and then remains in a fixed axial position as the actuator advances axially relative to the distal end of the container to provide the mixing stage e.g. to drive the proximal slidable wall of the container forward. The container housing may be prevented from advancing axially after the septum piercing stage when it may come into contact with the needle assembly.

In embodiments the rotating part rotates relative to a housing of the device. The rotating part may rotate relative to proximal and distal parts of the housing.

In some sets of embodiments the device comprises a part comprising an opening through which a distal end of the actuator must pass in order to cause a proximal slidable wall of the container to advance relative to the distal end of the container, wherein the distal end of the actuator may only pass through the opening when the part is in a given rotational alignment with the distal end of the actuator.

In these embodiments rotation of the rotating part may bring the distal end of the actuator into the given rotational alignment with the opening to permit the distal end of the actuator to pass therethrough. In this way, the distal end of the actuator may initially push against the region surrounding the opening before passing therethrough. When the part having the opening is coupled to the container this may result in the actuator driving the container forward axially relative to the distal end of the device as the actuator moves axially relative to the distal end of the device until the distal end of the actuator has come into the given rotational alignment with the opening as a result of the rotation of the rotating part to permit the distal end to move through the opening into the proximal end of the container to cause the mixing stage to occur e.g. to cause a proximal slidable wall of the container to advance.

In these embodiments the rotating part may be the distal end of the actuator or the part having the opening. However, in preferred embodiments the rotating part is the part having the opening.

In these embodiments the distal end of the actuator and the opening may define cooperating formations which only enable the distal end of the actuator to pass when in a certain rotational alignment with respect to the opening. For example the opening and the distal end of the actuator may be provided with cooperating shaped configurations in the manner of a key and slot. In some embodiments the opening defines one or more inwardly directed lugs and the distal end of the actuator comprises one or more slots wherein the distal end of the actuator may only pass through the opening when the lugs are rotationally aligned with the slots. Such arrangements may be advantageous as the actuator may comprise axially extending slots which are used to guide the axial movement of the actuator and inhibit rotational movement. The same slots may cooperate with the lugs of the other part. However other arrangements could be used. For example the distal end of the actuator may define a shape which has a rotationally asymmetric outline and the opening may define the same shape initially rotated through a given angle with respect to the end of the actuator.

In any of its embodiments the device may comprise guide means for influencing the movement of the rotating part. The movement of the rotating part may be controlled by the movement of a pin in a slot. The slot may be an inclined slot to result in rotation of the rotating part as it moves axially. In embodiments in which the rotating part is a part of a container housing, the container housing may comprise formations which cooperate with opposed formations to guide the rotational movement of the container housing. The opposed formations may be provided on a housing e.g. a distal housing of the device. For example, the container housing may comprise one or more lugs each of which rides in a cooperating inclined track. Alternatively, the container housing may comprise one or more grooves each of which cooperates with an inwardly projecting lug provided on a guide sleeve.

In embodiments the device may be arranged such that the rotating part does not rotate further after the transition between the septum piercing and mixing stages has occurred. The device may comprise means for constraining the part against further rotation. The constraining means may be of the type described earlier in relation to the actuator. In embodiments a formation of the rotating part may rotate into alignment with an axially extending slot for constraining the part against further rotation.

In embodiments the actuator may be inhibited from advancing further axially relative to the container once the mixing stage is complete and prior to commencement of an injection cycle. In some embodiments the device is arranged such that the mixing stage is complete when a proximal end of the actuator moves to a position in which it is flush with a proximal end of a housing of the device inhibiting further movement of the actuator into the housing. The user will then realise that the stage is complete as they will not be able to further mutually compress the housing and the actuator e.g. by advancing the actuator further by locating the proximal end of the actuator against a surface and urging the housing toward the surface.

In accordance with the invention in any of its embodiments having an actuator, the actuator may be arranged such that during the septum piercing and mixing stages it may only move axially in a first direction relative to the distal end of the device and not in an opposite axial direction. The direction of movement may be the direction relatively toward the distal end of the device e.g. into a housing.

In some embodiments in which an actuator is provided, the actuator is arranged to move in a series of discrete steps as it advances axially at least during the mixing stage, and preferably during the septum piercing and mixing stages. The actuator may advance in this manner during the septum piercing stage and the mixing stage. In these embodiments the actuator moves stepwise i.e.. incrementally rather than with a single smooth continuous movement under the action of a driving force.

In embodiments the actuator comprises a ratcheted portion which cooperates with an engaging arrangement to result in the actuator moving in a series of discrete steps. Such an arrangement may also provide single direction movement of the actuator as discussed above. The ratcheted portion may comprise a plurality of ratchet teeth extending along a length of a portion of the actuator. The ratchet portion may have an extent such that the engaging arrangement engages the ratcheted portion over the extent of travel of the actuator relative thereto during the septum piercing and mixing stages.

It will be appreciated that the engaging arrangement acts as a pawl. As a given tooth of the ratcheted portion encounters the engaging arrangement as the actuator is driven axially with respect to the engaging arrangement, the driving force causes a build up of strain in the engaging arrangement until it escapes over the tooth to allow the actuator to jump forward in a discrete step until the next tooth engages the engagement arrangement. The cooperation of the engaging arrangement with the ratchet arrangement therefore results in the actuator moving in a series of discontinuous or discrete steps. The arrangement which engages the ratchet formation may be of any suitable form. In embodiments the device comprises an annular member relative to which e.g. through which the actuator advances during the mixing stage, and preferably the septum piercing stage, which member engages the ratchet teeth of the ratcheted portion. The annular member may be a member which also constrains the actuator against rotation as mentioned previously.

In some embodiments the engagement arrangement comprises a clutch arrangement arranged such that the actuator may move relative to the clutch arrangement in a first direction when a driving force is applied to the actuator and not the clutch arrangement, and such that the actuator will move with the clutch arrangement when a driving force is applied to the clutch arrangement and not the actuator. The driving force will be an axial driving force and the actuator may move axially relative to the clutch arrangement. The clutch arrangement may prevent the movement of the actuator relative to the clutch arrangement in an opposite axial direction. In embodiments the clutch arrangement comprises a clutch ring. The clutch ring may comprise a diaphragm located radially between the clutch ring and the actuator to permit movement of the actuator in a first axial direction relative to the clutch ring when an axial force is applied thereto. The diaphragm may be a split ring. The diaphragm may flex to permit the ratchet teeth to pass as the actuator moves relative to the clutch ring. Alternatively, the clutch arrangement may comprise a single ring having angled resilient tabs, which performs the same ratchet function as the combination of a clutch ring and a split diaphragm.

The movement of the actuator in a series of discrete steps in this manner at least during the mixing stage is advantageous as this may help to encourage gas trapped in the container to be vented through the needle, further reducing the risk of gas being present in the fluid to be injected after mixing. The incremental movement may also facilitate mixing of the components of the chambers of the container, e.g. in the case of a lyophilized drug and solvent, promoting more complete dilution of the lyophilized drug. It is thought that this may be due to the slight jarring of the container as the actuator advances. A ratchet arrangement may also provide an audible signal to the user that the septum piercing and mixing is progressing.

It is believed that such arrangements are advantageous in their own right.

From a further aspect of the present invention there is provided;

an injection device, the device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use;

the device comprising;

an actuator, and a container;

wherein the container comprises a first chamber including a first component

and a second chamber including a second component, the first and second chambers being initially separated from one another by a seal to prevent mixing of the first and second components; wherein the device is arranged such that axial movement of the actuator relative to a distal end of the device provides a mixing stage in which the seal between the first and second chambers is breached to allow the first and second components to mix thereby providing a liquid comprising the first and second components for injection;

wherein the actuator comprises a ratcheted portion, and the device comprises an engaging arrangement which cooperates with the ratcheted portion to result in the actuator moving in a series of discrete steps during the mixing stage.

The present invention in accordance with these further aspects may include any of the features described in relation to the first aspect of the invention to the extent they are not mutually inconsistent. Thus the device of this further aspect may, for example, comprise a needle, and may be configured to provide a septum piercing stage prior to the mixing stage. The actuator moves into the container during the mixing stage e.g. to advance a proximal slidable wall of the container.

In accordance with any of the aspects and embodiments of the invention the device may comprise a viewing window to permit viewing of the interior of the container before actuation of the device and after the septum piercing and mixing stages. The viewing window may permit viewing of the region of the seal and the second chamber distal thereto. This may allow an observer to check that the content of the chambers has mixed, and during an injection cycle, verify that the content of the container distal of the seal has been dispensed. The window should be of dimensions suitable to permit viewing of the content of the container even after the container has moved axially during the septum piercing stage, and in embodiments rotationally.

From a broad aspect, it may be seen that the present invention may, in any of its embodiments, provide an injection device in which the septum piercing and mixing stages occur under the influence of a manual operation by the user i.e. under the input of manual energy. The manual operation is not simply an initial activating step. The septum piercing and mixing stages proceed as a result of the input of manual energy input by a user. In embodiments the manual operation may be the operation of an actuator of the device. The manual operation may be the manual driving of the actuator relative to a distal end of the device such that the septum piercing and mixing stages occur under the influence of the actuator. The manual driving of the actuator may comprise the mutual axial compression of the actuator and another part of the device. The part of the device may be a housing. The manual operation may be the driving of the actuator into a proximal end of the housing. The septum piercing and mixing stages may occur under the influence of a single manual operation carried out by a user. For example the septum piercing and mixing stages may occur as the actuator is caused to travel over an increasing distance relative to the distal end of the device, and/or with increasing mutual compression of the actuator and a part of the device e.g. a housing. While the septum piercing and mixing stages preferably occur under the action of a manual operation by the user, a subsequent injection cycle is preferably delivered automatically as described below.

In accordance with a further aspect the present invention provides an injection device; the device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use;

the device comprising;

a container;

a septum sealing a distal end of the container;

and a needle located distal to the container;

wherein the container comprises a first chamber including a first component

components for injection;

wherein the septum piercing stage and the mixing stage occur under the influence of a manual operation by the user,

and preferably wherein the device is arranged to automatically perform an injection cycle after the mixing stage comprising the steps of advancing the needle for insertion, dispensing the mixed composition in the container, and preferably retracting the needle.

The present invention in accordance with these further aspects may include any of the features described in relation to the other aspects of the invention to the extent they are not mutually inconsistent.

From another broad aspect, in accordance with the invention in any of its aspects or embodiments, it may be seen that the present invention may provide a device in which the container is caused to rotate during a septum piercing stage. For example the container may rotate as the container and the needle are mutually compressed to caused the needle to pierce the septum.

In accordance with the invention in any of its aspects or embodiments, once the septum piercing and mixing stage are complete the device may be used to deliver an injection of the composition comprising the mixed first and second components. This may be achieved in any suitable manner. As discussed above, in some sets of embodiments the device may not be used to deliver an injection until a guard is displaced. This may result in removal of a needle shield to expose the needle ready for use. In some embodiments the guard may block an activation means of the device, and is removed to permit activation of the device.

In some sets of embodiments the device is arranged to perform an automatic injection cycle comprising the steps of advancing the needle for insertion, dispensing the composition in the container, and retracting the needle. It will be appreciated that alternatively the device could perform only certain steps automatically requiring a step or steps to be conducted manually. For example needle retraction might be performed manually. However preferably each of the steps of advancing the needle for insertion, dispensing the composition and retracting the needle occur automatically. In some cases user intervention might be required to move between stages. However preferably the device transitions automatically between the stages. The step of dispensing the composition may comprise the step of driving a slidable proximal wall of the container into the container to cause the composition to be dispensed.

In embodiments, the device comprises an actuator and driving means for driving the actuator forward axially to advance a proximal slidable wall of the container within the container for dispensing a mixed composition contained in the container. In embodiments having an actuator for controlling the septum piercing and mixing stages, as discussed previously, the actuator for dispensing the mixed composition may be a different actuator, or preferably the same actuator.

Preferably the device is arranged such that during operation of the device, a driving force is transmitted from the driving means to the actuator during the dispensing stage, and such that a driving force is not transmitted to the actuator during the retraction stage to allow retraction of the needle.

The injection device may comprise a drive coupling arrangement between the driving means and the actuator, wherein the drive coupling arrangement comprises a drive coupling part selectively transmitting or not transmitting force from the driving means to the actuator depending upon the position of the coupling part, preferably a rotational position thereof. In these embodiments the drive force is transmitted or not transmitted as a result of the rotational position of the coupling part, and hence there is a transition between stages of the injection cycle caused by the position of the coupling part.

In accordance with a further aspect of the invention there is provided an injection device, the device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use;

the device comprising;

a container; an actuator;

a septum sealing a distal end of the container;

and a needle located distal to the container;

wherein the container comprises a first chamber including a first component

and a second chamber including a second component, the first and second chambers being initially separated from one another by a seal to prevent mixing of the first and second components;

components for injection;

wherein the device is arranged to perform an injection cycle after the mixing stage, the injection cycle comprising the steps of advancing the needle for insertion, dispensing the composition in the container, and retracting the needle;

wherein the device comprises driving means for driving the actuator forward axially to cause the composition contained in the container to be dispensed; wherein the device is arranged such that during the injection cycle, a driving force is transmitted from the driving means to the actuator during the dispensing stage, and such that a driving force is not transmitted to the actuator during the retraction stage to allow retraction of the needle;

wherein the automatic injection device comprises a drive coupling arrangement between said driving means and the actuator;

wherein said drive coupling arrangement comprises a drive coupling part selectively transmitting or not transmitting force from the driving means to the actuator depending upon a position of the coupling part, preferably a rotational position thereof.

The present invention in accordance with this further aspect may include the features of any of the other aspects or embodiments earlier described.

In accordance with any of the aspects or embodiments of the invention, as described in relation to the mixing stage, the actuator may directly or indirectly cause the slidable wall to advance for dispensing the content of the container.

The driving means may be of any suitable form. In embodiments the driving means comprises spring means. The spring may be a coil spring.

In embodiments the injection cycle must be initiated by user intervention. The initiation may be provided by a single action of the user, such as a button press etc. In some sets of embodiments the device comprises a housing, and the injection cycle is initiated by axial movement of a proximal part of the housing relative to a distal part of the housing. The user may locate the distal part of the housing against the skin and push down dn the proximal part of the housing to initiate the injection cycle.

In some sets of embodiments the initiation step may be operable to release a catch or detent which restrains a resilient force of a driving means.

In some sets of embodiments the drive coupling arrangement comprises first and second parts which are configurable such that a driving force can be selectively transmitted or not transmitted between them in use depending upon the relative positions of the parts, preferably the relative rotational positions thereof, wherein the first and second parts are arranged such that during operation of the device, a driving force is transmitted between the first and second parts during the dispensing stage for applying a driving force to the actuator, and such that a driving force is not transmitted between the first and second parts during the retraction stage to allow retraction of the needle. The transition between states of the injection cycle is caused as a result of the change in the relative positions of the parts.

The driving means may be arranged to act on the first part. The driving means may be arranged to act directly thereon. The first part may directly contact the second part for transmitting a driving force thereto in use.

The second part may circumferentially surround the actuator. The first part may be arranged to surround the second part.

In embodiments the second part is connected to the actuator and is not movable relative to the actuator. In this manner, a driving force transmitted to the second part may be

transmitted to the actuator. The second part could be a part of the actuator. However, in preferred embodiments the second part is a separate part mounted to the actuator. In embodiments the second part is arranged to clutch the actuator whereby the actuator may be advanced relative to the second part in a first direction relative to the distal end of the device when an axial force is applied to the actuator and not the second part during the septum piercing and mixing stages, and wherein the second part may not move axially relative to the actuator when an axial force is applied to the second part and not the actuator. The second part may be a clutch ring. In some sets of embodiments described above the actuator comprises a ratcheted portion and the second part may be arranged to engage the teeth of the ratchet arrangement to cause the actuator to move with the second part when an axial force is applied to the second part and not the actuator. A diaphragm may be located radially between the second part and the actuator to permit single direction axial movement of the actuator relative to the second part when an axial force is applied to the actuator and not the second part. In embodiments the second part is provided by the engaging arrangement e.g. a clutch ring arranged to engage the ratcheted portion as discussed above. Regardless of the form of the second part, in embodiments in which the first and second parts rotate relative to one another, in some embodiments the second part is not rotatable relative to the actuator. In embodiments the second part comprises a formation e.g. one or more lugs which cooperates with a formation of the actuator e.g. a corresponding axially extending track of the actuator to constrain the second part against rotation relative to the actuator.

In embodiments in which the first and second pars rotate relative to one another, the first part may be arranged to rotate relative to the second part under the action of the driving force transmitted thereto by the driving means in use, the first part being rotatable into a given rotational position relative to the second part in which a driving force is no longer transmitted between the first and second parts in use. The second part may be arranged to retract relative to the first part when the first part ceases to transmit a driving force thereto in use. The device may be arranged such that once the driving force ceases to be transmitted from the first part to the second part in use, the actuator and container are free to move rearwardly with the second part thereby retracting the needle. The device may comprise biasing means e.g. return springs arranged to cause the container to retract when the driving force is no longer applied to the actuator in use. The second part and the actuator will then retract with the container.

The device may be arranged such that once the driving force is no longer transmitted from the first part to the second part in use, the driving force continues to be applied to the first part but is no longer effective in driving the first part axially.

In some sets of embodiments the movement of the first part relative to the second part is guided by the travel of a pin in a slot. In some embodiments the first part rotates relatively to the second part until the second part reaches a rotational position in which a pin of the second part is brought into alignment with an axially extending slot to permit the second part to retract relative to the first part.

In embodiments the device is arranged such that, depending upon a configuration of the drive coupling arrangement, the container is driven forward during the needle advancement stage, and the actuator is driven forward relative to the container e.g. to cause the proximal slidable wall of the container to advance within the container, during the dispensing stage for dispensing the composition contained in the container. Such arrangements are desirable as they may mean that there is no resultant axial force on the slidable proximal wall of the container during the needle advancement stage. This may avoid premature dispensing of liquid before the needle has been advanced to an intended depth. The device may be configured such that the needle is advanced by a predetermined axial distance before the proximal slidable wall is driven into the container to dispense liquid.

These arrangements may provide distinct needle advancement and dispensing stages depending upon the state of the drive coupling arrangement. In some sets of embodiments a driving force transmitted to the proximal slidable wall is selectively effective to drive the slidable wall into the container wherein during the needle advancement stage the container is driven forward to advance the needle and wherein during the dispensing stage the proximal slidable wall is driven into the container to dispense liquid. In some sets of embodiments the drive coupling arrangement is arranged to transmit a driving force to the container during the needle advancement stage, and to transmit a driving force to the actuator and not the container during said dispensing stage to dispense liquid in the container e.g. by driving the slidable wall into the container.

In some sets of embodiments a transition between the needle advancement and dispensing stages is controlled by the movement of a part of the drive coupling arrangement. The movement is preferably rotational, and more preferably a simultaneous rotational and axial movement. The part could be the first part. In other embodiments the drive coupling

arrangement may comprise a third part, wherein the first part is arranged to transmit a driving force to the third part, wherein the third part is arranged to move under the action of the driving force between a first position in which the driving force is transmitted to the container, and a second position in which the driving force is not transmitted to the container. The first and second positions may be rotational positions. The device may be arranged such that a driving force transmitted from the first part to the second part is selectively effective to drive the slidable proximal wall into the container depending upon the rotational position of the third part. The first part may engage the third part.

The third part may be arranged to be rotatable under the action of the driving force transmitted thereto, and the first part is arranged to rotate in an opposite sense to the third part under the action of the driving force.

In some sets of embodiments the first part, or where provided the third part rotates from a position in which it may not move axially relative to the container to a position in which it may move axially relative to the container. In embodiments the first or third part may rotate into alignment with an axially extending slot in a container housing. In this manner the driving force transmitted to the first part may initially cause the first or third part to cause the container to advance thus advancing the needle until the first or third part has rotated to a position in which it moves relative to the container. This may allow the actuator to advance relative to the container to drive the proximal slidable wall of the container forward to dispense liquid from the container under the action of the driving force transmitted from the first part to the second part.

The device may comprise guide means for influencing the movement of the first part and/or the third part under the action of the driving force. The movement of the first part and/or the third part under the action of the driving force may be guided by the travel of a pin in a slot.

It will be appreciated that during the septum piercing stage the container will have moved forward axially relative to the parts of the drive coupling arrangement. Accordingly the first part, second part and third part if present may be arranged to initially advance axially under the action of the driving force to enable the third part or otherwise first part to come into engagement with the proximal end of the container or container housing.

The present invention extends to the use of a device in accordance with the invention in any of its embodiments. In embodiments the method may comprise the steps of carrying out a manual operation to cause the device to carry out the septum piecing an mixing stages. The manual operation may comprise causing an actuator to move axially relative to the distal end of the device and/or mutually axially compressing an actuator and a housing of the device. The method may comprise locating the device such that a proximal end of an actuator is located against a surface, and grasping a housing of the device and urging the housing toward the proximal end of the actuator to cause the septum piercing and mixing stages to take place as the actuator moves axially relative to the distal end of the device. The method may further comprise initiating an automatic injection cycle after the mixing stage.

The present invention extends to a kit of parts for the device in accordance with the invention in any of its aspects or embodiments. The kit may or may not include the container. In accordance with a further aspect the present invention provides a kit of parts for the device in accordance with the invention in any of its aspects or embodiments, wherein the kit does not include the container.

Some preferred embodiments of the invention will now be described by way of example only, and with reference to the accompanying drawings in which:

Fig. 1A is a perspective view from one side of the automatic injection device in accordance with a first embodiment of the invention prior to actuation of the device to commence the septum piercing stage;

Fig. 1B is a view corresponding to that of Fig. 1 A but taken from the proximal end to show certain features of the actuating rod in more detail and with the device rotated from the position shown in Fig. 1A;

Figures 2-25 illustrate various stages of the assembly of the device of Figures 1 A and 1 B in more detail;

Fig. 2 is a cut-away view from one side of a cartridge which is used in the device of Fig. 1 schematically illustrating the content of the chambers of the cartridge;

Fig. 3 illustrates the cartridge of Fig. 2 located adjacent a needle assembly of the device without illustrating the content of the chambers;

Fig. 4 is a view similar to that of Fig. 3 but showing the relationship between the needle and the cartridge in more detail, and with certain parts of the needle assembly removed for clarity;

Fig. 5 is a perspective view of the assembly of Fig. 3 further assembled with a cartridge housing; Fig. 6 is a view of the assembly of Fig. 5 with a slip ring additionally assembled to the proximal end of the cartridge housing;

Fig. 7 is a view illustrating the cartridge housing and slip ring in more detail taken from the rear of the slip ring shown in Fig. 6, and with the cartridge housing rotated from the position shown in Figure 6, and omitting the needle assembly;

Fig. 8 is a perspective view of the assembly of Fig. 6 after the actuating rod and clutch ring have been added;

Fig. 9 is a detailed view in the region of the attachment between the actuating rod and the rear end of the slip ring of Figure 8 showing certain features of the actuating rod and slip ring in more detail, and with the clutch ring surrounding the diaphragm of the actuating rod removed for ease of reference;

Fig. 10 is a view showing in more detail the actuating rod in the region of the clutch ring of Fig. 8 with the clutch ring shown in cross-section to illustrate the position of the diaphragm therein;

Fig. 11 is a view showing in more detail the region of the interface between the actuating rod and the slip ring during the septum piercing stage, with the clutch ring removed for ease of explanation;

Fig. 12 is a perspective view of the cartridge housing shown in Fig. 5 after a front housing has additionally been assembled thereto;

Fig. 13 is a view corresponding to Fig. 12 but with a section taken through the front housing through the lower of the barbs 82 indicated in Fig. 12 to illustrate the way in which the front housing cooperates with the needle assembly;

Fig. 14 is a view corresponding to that of Fig. 12 but illustrating the components after the lug of the cartridge housing has started to travel along the track of the front housing as the cartridge housing is moved axially relative to the front housing during the septum piercing stage;

Fig. 15 illustrates the assembly of Fig. 12 with the actuating rod, slip ring and clutch ring added;

Fig. 16 is a view similar to that of Fig. 15 but with a guard added to the front housing, and with the clutch ring removed for ease of reference;

Fig. 17 is a view corresponding to that of Fig. 15 but with the guard located over the proximal end of the cartridge housing;

Fig. 18 is a view corresponding to that of Fig. 17 but showing the assembly after the actuator rod pusher has been added;

Fig. 19 is a more detailed view showing the assembly of Fig. 18 in the region of the actuator rod pusher with the needle pusher removed for ease of reference, illustrating the components of the actuator rod pusher in more detail; Fi^'g. 20 is a view similar to that of Fig. 18 showing some aspects of the rear part of the assembly in more detail, and with a spring retainer added;

Fig. 21 corresponds to the view of Fig. 20 showing the whole length of the assembly and with the main spring added;

Fig. 22 corresponds to the view of Fig. 21 but with return springs located between the container housing and the front housing;

Fig. 23 is another view of the assembly of Fig. 20 taken from the rear end to illustrate certain features of the rear part of the assembly, and with the actuator rod pusher cut away to show its cooperation with the clutch ring and diaphragm;

Fig. 24A is a view showing certain components of the rear of the assembly in more detail, including the rear housing, and showing the cooperation between the spring retainer, and the actuating rod pusher before the device is actuated to commence an injection cycle, and with the main spring removed for ease of reference;

Fig. 24B is a view corresponding to that of Fig. 24A after the injection cycle has been actuated by movement of the rear housing axially toward the spring retainer, showing the movement of the actuating rod pusher away from the spring retaining means, but with the spring omitted for ease of reference;

Fig. 25 illustrates the assembly of Fig. 22 after a guide sleeve has been added;

Fig. 26 is a perspective view of an alternative cartridge housing and front housing; and

Fig. 27 is a perspective cutaway view of an alternative ratchet mechanism.

Figure 1A illustrates an automatic injection device in accordance with an embodiment of the invention. The device is an automatic injection device for injecting a reconstituted lyophilized drug.

Figure 1A illustrates the device in the form supplied to a user, after removal from any secondary packaging but before the septum piercing, mixing or any injection delivery steps have been carried out. The device has a proximal end which is located furthest from the skin of a user when an injection is delivered in use. The opposite end is the distal end from which the needle projects in use to deliver an injection and is closest to an injection site in use. The proximal and distal ends of the device may also be referred to as the front and rear ends of the device.

The device 1 is a pen-shaped device having a rear housing 3 which may be gripped by a user in use. A actuating rod 55 extends from the proximal or rear end of the housing to enable it to be caused to enter the housing by a user in order to actuate the device as described in more detail below.

The device includes a dual chamber cartridge which is not visible in Figure 1A, including the lyophilized drug and a solvent which must be mixed to provide a liquid for injection through the needle in use. The cartridge is disposed in a cartridge housing 40, a part of which is visible in Figure 1A.

The device also includes a viewing window 9 which enables the user to view the dual chamber cartridge located therein in order to verify the position of the pistons of the cartridge during use of the device after the mixing stage and before and after delivery of the drug.

The device includes at its distal end a guard 90 having a formation to facilitate gripping by a user. The guard 90 must be rotated and slid off the front of the device axially to remove the needle shield, and to permit movement of the rear housing 3 to allow actuation of the device, before the device may be used to deliver an injection. In alternative embodiment shown in Figure 26, a guard 190 is arranged to be squeezed and slid off the front of the device by a user. The rear housing 3 is movable a small distance axially relative to the front housing 80 when the guard 90, 190 is removed to initiate an injection cycle.

Located radially inwardly of the guard 90, 190 is a front housing 80, 180 of the device having a distal end which is located against the skin of a user when an injection is delivered in use. The front end of a needle shield 35 and the needle 32 disposed therein may be seen within the front housing 80, 180.

The rear housing 3 houses the mechanism of the device which enables the device to automatically carry out the steps of pushing a needle on to a dual chamber cartridge and then reconstituting the lyophilized drug therein when the actuating rod 55 is caused to move into the rear housing 3 from the position in Figure 1 A. The device is then primed ready to be used to deliver an automatic injection cycle including the steps of advancing the needle for insertion, delivery of the reconstituted liquid composition through the needle and finally needle retraction.

Figure 1 B is a view similar to Figure 1A but showing the device from the rear end, more clearly illustrating the features of the actuating rod 55, which includes a ratcheted portion as described later.

The features of the device will now be described in more detail. The construction of the front part of the device will first be described by reference to Figures 1 A to 15.

Figure 2 illustrates the dual chamber cartridge 11 of the device prior to operation of the device. The cartridge 11 has a glass main body 22 defining a front shoulder 16. The proximal end of the cartridge is plugged by a slidable wall in the form of a proximal piston 21. A proximal plug 24 is located distally to the proximal piston 21.

The dual chamber cartridge includes a proximal chamber 13 and a distal chamber 15. The proximal and distal chambers are separated from one another by a seal in the form of a distal piston 23 when the cartridge is in its initial condition as shown in Figure 2 prior to any reconstitution. The proximal chamber 13 is defined between the distal end of the proximal piston 21 and the proximal end of the distal piston 23. The distal piston 23 prevents fluid communication between the proximal and distal chambers. The proximal chamber 13 includes a solvent 19 indicated by the dotted region in Figure 1. The front or distal chamber 5 includes a plug of lyophilized drug 17, in the form of a compacted powder located distally of the piston 23, with an air gap 18 extending between the distal end of the lyophilized drug 17 and a front plug 27 of the cartridge. The front plug 27 includes a septum 38 which provides a fluid-tight seal at the distal end of the cartridge. The septum 38 is in the form of a rupturable membrane which may be pierced by a needle in use to place the needle in fluid communication with the interior of the cartridge 11.

The cartridge includes a by-pass channel 25 in the region of the lyophilized drug 17. This channel may allow solvent 19 from the proximal chamber 13 to flow into the distal chamber 15 and mix with the lyophilized drug 17 when the distal piston 23 is displaced axially towards the distal end of the cartridge in use. The distal end of the distal piston 23 initially lies behind the proximal end of the channel 25. In use the distal piston 23 may be moved distally from the position shown in Figure 1 pushing the lyophilized drug 17 towards the distal end of the device until the proximal end of the piston 23 is level with the channel 25 to permit fluid to move through the channel between the chambers.

Although the invention will be described in the context of a device for delivering a lyophilized drug, and which includes a dual-chamber cartridge having a lyophilized drug therein which must be reconstituted prior to use, it will be appreciated that the device of the present invention may be used with other types of cartridge, which need not necessarily include the lyophilized drug/solvent components in its chambers. For example the invention is equally applicable to the use of cartridges which include two liquid components which must be mixed prior to use of the device to deliver an injection, or ones in which the components to be mixed are a powder and a liquid respectively. Such arrangements would proceed in the manner described with respect to the embodiment involving the lyophilized drug/solvent combination, except that the cartridge would include an additional liquid, or a powder in the distal chamber 15 in the place of the lyophilized drug 17.

The device is particularly applicable to so-called "Vetter" cartridges which are of the form shown in Figure 2, and may be used to deliver drugs which are formed by mixing two components initially located in proximal and distal chambers, and being respectively a lyophilized drug and a solvent, or alternatively where the first and second components are different liquid components, or a liquid and a solid e.g. a powder which is not a lypophilized substance. Such cartridges typically have a volume in the range of from 0.5 mm to 1.5 mm in the proximal chamber and 0.5 mm to 1.3 mm in the distal chamber. Such cartridges are available from Vetter Pharma International GmbH or Vetter Pharma USA Incorporated. Such cartridges may be incorporated in the device without modification. Figure 3 shows the relationship of the cartridge 11 to a needle assembly 34 located at the distal end of the device. The content of the chambers is not schematically shown in Figure 3. The needle assembly 34 includes a seal in the form of a rupturable paper membrane 36 at its proximal end which acts to seal the needle assembly and maintain a sterile condition of the needle before the needle is connected to the cartridge. The needle assembly 34 includes a needle 32 which is held in a friction-fit to a needle retainer 30 to prevent axial movement of the needle relative thereto. The needle has points at both the proximal and distal ends thereof. The needle may be an integral needle having the proximal and distal points, or may be provided by proximal and distal needles in fluid communication with one another. Radially outwardly of the needle retainer 30 is a needle shield 35. The needle shield protects the needle prior to use, forming a seal with the paper membrane 36 to retain sterility of the needle. The needle shield 35 also prevents accidental needle stick injuries. The needle shield includes a collar 37 at the proximal end thereof. The needle 32 is not movable axially relative to the other components of the needle assembly, being secured to the needle retainer which in turn is secured in fixed relation to the shield 35.

The needle assembly 34 is a standard unit which may be bought off the shelf.

In the device as supplied to a user, and prior to any actuation of the device, the proximal end of the needle 32 is located distally of the distal end of the stopper 27 at the front of the cartridge, and is axially spaced therefrom. Before the device may be used, the cartridge 11 and the distal end of the needle must be moved together to push the proximal end of the needle 32 onto the septum 38 to rupture the membrane 36 to place the needle in fluid communication with the interior of the chamber 15.

The relative positions of the cartridge 1 1 and the needle 32 may be understood better by reference to Figure 4 which illustrates the needle 32, needle retainer 30 and the cartridge 11 with the needle shield 35 and membrane 36 removed for ease of reference. The content of the chambers of the cartridge is not indicated in Figure 4. Here it may be seen that the proximal end of the needle 32 is spaced axially from the distal end of the septum 38 such that the cartridge 1 1 and needle 32 must be moved relatively together in an axial direction in order to push the needle onto the cartridge and pierce the septum 38.

As will be described in more detail below, the needle assembly 34 and hence the needle 32 is maintained in a fixed axial position relative to a distal end of the device and the cartridge 1 1 moved axially in relation to the distal end of the device in order to accomplish this.

The cartridge 1 1 is located in a cartridge housing 40 which is shown in Figure 5. The cartridge housing 40 includes a distal portion and a proximal portion separated by a collar 43. The proximal end terminates in a connecting portion 44 of smaller cross sectional diameter than the main body of the housing 40. The proximal and distal sections of the cartridge housing 40 includes certain formations to enable the cartridge housing to cooperate with other parts of the mechanism of the device.

The distal part of the syringe housing includes lugs 45 at its distal end. While only one lug 45 may be seen in the view of Figure 5, in fact three identical lugs 45 are equally spaced around the circumference of the cartridge housing 40. The lugs are at the same axial position along the length of the cartridge housing.

Alternatively, rather than lugs 45, the distal part of the syringe housing may include grooves 145, one of which is shown in the embodiment of Figure 26. The function of the lugs 45 and the grooves 145 will be discussed in more detail below.

The cartridge housing also includes at its distal end a closed ended bore 49 terminating in the collar 43. An identical bore is located on the opposite side of the housing at 180 degrees around the circumference from the bore 49 shown.

The distal end of the housing also includes a dowel 47. A similar dowel is located on the opposite side of the housing.

At its proximal end, the cartridge housing includes an axial slot 42 extending from the proximal end of the main body of the housing 40. An identical slot is provided on the other side of the housing at 180 degrees to that shown. The connecting portion 44 defines a set of resilient legs 78 defining hooks 39 at their proximal ends.

In use the cartridge 11 may be slid into the cartridge housing through the proximal end thereof with the resilient legs of the connecting portion 44 flexing to enable the cartridge to pass. The cartridge will then be retained at its proximal end relative to the cartridge housing by the hooks 39 which hook over the proximal end of the cartridge. The hooks 39 at the proximal end of the cartridge housing may be seen in Figure 9 and 12 more clearly.

The distal end of the cartridge housing defines a retaining collar 33 which engages against the shoulder 6 at the distal end of the cartridge to constrain the cartridge against axial movement in the distal direction.

The cartridge housing 40 also includes a slot 41 which is positioned to coincide with the position of the window 9 in the rear housing 3 to allow the user to see through the body of the cartridge housing in order to observe the position of the proximal and distal pistons 21 , 23. The window should have a length which permits the user to see at least the distal piston 23 prior to use of the device, and the portion of the cartridge body extending distally therefrom towards the stopper 27 so that they may observe the movement of the piston during reconstitution and subsequently before and after delivery of an injection. The slot 41 extends axially through the collar 43 and into the distal portion of the cartridge housing to terminate proximally of the lug 45.

Figure 6 is a similar view to Figure 5, but showing a slip ring 46 mounted over the connecting portion 44 of the cartridge housing 40 to be flush with the main body of the proximal end of the cartridge housing. Figure 7 is a view of the cartridge housing 40 with the slip ring 46 mounted thereto from the proximal end illustrating certain features of the slip ring and cartridge housing in more detail. The slip ring 46 defines a slot 48 which is aligned with the slot 42 to provide a continuous axially extending slot starting at the proximal end of the slip ring 46. A similar slot is provided on the other side of the slip ring to cooperate with the other slot 41.

The slip ring 46 is keyed to the cartridge housing 11 such that it may not rotate relative thereto. The proximal or rear end of the slip ring 46 includes three lugs 51 disposed around its circumference at equal intervals on the interior surface thereof, one of which is visible in Figure 7. These lugs 51 cooperate with the slots defined between the legs of the connecting portion 44 of the cartridge housing to retain the slip ring 46 in a fixed rotational position with respect to the housing 11. The slip ring 46 may not move axially relative to the housing by virtue of the cooperation of its distal end with the shoulder defined at the proximal end of connecting portion 44 of the cartridge housing. The proximal end of the slip ring 46 defines three inwardly extending lugs 50 at equal intervals around its circumference.

Moving on to Figure 8, actuating rod 55 is mounted to the rear of the assembly shown in Figure 6. The actuating rod 55 includes a proximal portion 64 and intermediate portion 62 and a distal portion 66. The proximal portion 64 is smooth surfaced. The intermediate section 62 is ratcheted, having a plurality of sloping teeth 70. The actuating rod 55 defines three axially extending slots 60 equally spaced around the circumference of the rod, and extending from the distal end thereof along the length of the intermediate and distal portions. Figure 9 shows that the distal portion of the actuating rod 55 defines a step 75 and a distal end portion 74 of smaller cross sectional diameter distal thereto. The slots 60 terminate at the step 75.

A clutch ring 57 is mounted over the actuating rod 55 initially being located at the distal end of the ratcheted intermediate region 62. A split diaphragm 74 is located so as to circumferentially surround the actuating rod 55, being disposed radially between the clutch ring 57 and the actuating rod 55. The diaphragm ring 74 is shown in Figure 9 with the clutch ring 57 removed, while Figure 10 illustrates the relationship between the clutch ring 57, the diaphragm ring 74 and the rod 55. The clutch ring and diaphragm permit the rod 55 to advance only in the forward direction i.e. toward the distal end of the device and not in the reverse direction relative to the clutch ring 57 when an axial force is applied to the proximal end of the rod 55 and not the clutch ring 57. The diaphragm 74 is split to permit single direction movement of the teeth 70 relative thereto, flexing to allow the teeth to pass. The user will note a clicking sound as the actuator advances in a stepwise fashion. If an axial force is applied to the ring 57 and not the rod 55 the ring 57 will grip the teeth 70 and urge the rod forward with the ring 57.

The clutch ring 57 defines three radially inwardly projecting lugs 58 disposed at equal intervals around its circumference which are located in the axially extending slots 60 of the actuating rod 55. This ensures that the ring 57 is maintained in a fixed rotational position with respect to the actuating rod 55. The ratcheted portion 62 has a length such that the clutch ring 57 is engaged with the proximal end of the ratcheted portion once the proximal end of the actuating rod has become flush with the proximal end of the rear housing 3 at the end of the mixing stage.

The ring 57 also includes a radially outwardly projecting lug 59.

In an alternative embodiment shown in Figure 27, the clutch ring 57 and the split diaphragm 74 may be combined into a single ring 157. The ring 157 includes angled resilient tabs 174, which perform the same ratchet function as the split diaphragm 74. In the same manner as the clutch ring 57, the single ring 157 includes lugs 58, 59. The single ring 157 functions in exactly the same way as the clutch ring 57 and split diaphragm 74. As such, any discussion regarding the function of the clutch ring 57 and the split diaphragm 74 applies equally to the single ring 157.

The attachment of the actuating rod 55 to the proximal end of the cartridge housing 40 may be seen in more detail in Figure 11.

The distal end portion 72 of the actuating rod 55 distal of the step 75 is inserted through the opening at the proximal end of the slip ring 48 such that a front face thereof engages the proximal piston 21 of the cartridge. The actuating rod 55 is initially in the position shown in Figure 11 , in which it is prevented from moving axially relative to the slip ring 46 and hence cartridge housing 40 as a result of the engagement between the step 75 and the inwardly projecting lugs 50 at the proximal end of the slip ring. However the lugs 50 and the slots 60 in the actuating rod 55 which extend rearwardly from the step 75 are configured such that when the cartridge housing and slip ring rotate relative to the actuating rod, the lugs 50 may be brought into alignment with the distal ends of the slots 60 to permit the actuating rod to move axially relative to the cartridge housing and slip ring. The distal end portion 72 may then advance into the cartridge housing to advance the proximal piston 21.

The front assembly of a first embodiment of the device will now be described in more detail with respect to Figures 12 to 16. For ease of explanation, Figures 12 to 14 do not show the slip ring 46 or actuating rod 55.

A front housing 80 is located over the front or distal end of the cartridge housing 40. The distal end of the front housing is arranged to engage the user's skin in use when an injection is delivered.

The front housing 80 is attached to the cartridge housing 11 in a manner which permits the cartridge housing 11 to rotate relative to the front housing 80 in a direction anticlockwise from the position shown in Figure 12. The front housing 80 is retained to the front end of the cartridge housing 40 by engagement of the lugs 45 in respective inclined tracks 84 at the proximal end of the front housing 80. Three inclined tracks 84 are provided at equally spaced intervals around the circumference of the front housing for receiving each of the lugs 45. The proximal end of the front housing 80 defines a step 93 which faces the collar 43 of the cartridge housing 11. The front housing defines a pair of tracks on the inner surface thereof which are not visible in the Figures, into which the dowels 47 of the cartridge housing 40 may move after rotation of the cartridge housing at the end of the septum piercing stage to constrain the cartridge housing such that it may only move axially relative to the front housing during the subsequent injection cycle when it is advanced to advance the needle.

The proximal end of the front housing also includes an L-shaped slot having a circumferentially extending portion 86 which communicates at one end with an axially extending linear portion 88 which extends toward a distal end of the front housing 80. There are three such L-shaped slots located at equal intervals around the circumference of the front housing as may be seen more clearly in Figure 15 for example. A pair of circumferentially extending slots 91 are located at the proximal end of the front housing at 180 degrees to one another.

The front housing includes three barbs 82 located at equal intervals around the circumference of the housing. A stop 83 is provided on the front housing which acts to limit the relative axial movement of the rear housing 3 and the front housing 80 when the rear housing 3 is moved axially relative to the front housing 80 to actuate the device after removal of the guard 90.

The front housing is shown cut-away in a section taken in the region of the lower of the barbs 82 in Figure 13 to illustrate the cooperation between the front housing and the needle assembly. As may be seen in more detail in Figure 13, the proximal ends of the barbs engage distally to the collar 37 of the needle shield 35 of the needle assembly to prevent movement of the shield and needle toward the distal end of the device as the needle is pushed on to the cartridge 11. The barbs 82 resiliency grip the needle shield 35 holding it in a fixed axial position relative to the front housing 80 and the distal end of the device, and preventing its movement axially toward the distal end of the device. As described below, the barbs 82 are urged toward the needle shield by a guard 90 located over the front housing 80. The front housing 80 also defines a lip proximally of the barbs 82 such that the collar 37 is sandwiched between the lip and the barbs 82 to prevent it moving axially relative to the front housing toward the proximal end of the device. The front housing 80 and the guard 90 cooperate to maintain the needle in a fixed axial position relative to the distal end of the device during the mixing stage as the actuating rod 55 moves into the rear housing 3 to advance the pistons of the cartridge 11.

Figure 14 is a view similar to Figure 12 but showing the relative positions of the cartridge housing 40 and the front housing 80 when the cartridge housing 40 and cartridge therein have started to rotate relative to the front housing with the lug 45 having travelled a small distance along the inclined track 84. This view also shows the position of the collar 37 of the needle shield 35 more clearly. Figure 15 is a similar view to Figure 12 but showing the actuating rod 55, clutch ring 57 and slip ring 46 assembled to the rear of the cartridge housing 40.

Figure 16 illustrates the assembly when the guard 90 has been assembled to the front or distal end thereof. The clutch ring 57 is not shown in Figure 16. The guard 90 includes a ring having formations 94 to aid gripping by a user. The guard 90 is in its initial position as supplied to a user in Figure 16 in which it prevents the device from being initiated to deliver an injection, as the guard 90 prevents the rear housing 3 from being moved axially relative to front housing 80. The guard 90 includes three claws 92. When the guard 90 is in its initial position, the claws 92 are located at the blind ends of the circumferentially extending portions 86 of the L-shaped slots of the front housing. The claws 92 are initially located at a position axially behind and spaced from the collar 37 of the needle shield 35.

In order to remove the guard 90 a user must therefore twist the guard rotating it to bring the claws to the start of the axial portion 88 of the L-shaped slots before pulling it off axially. As the guard is moved axially relative to the front housing, the proximal ends of the claws 92 will engage behind the collar 37 to pull off the needle shield 35 with the guard 90. This will leave the needle exposed, but still in a retracted position relative to the front of the front housing 80 ready to commence an injection cycle.

Between the claws 92, the guard 90 includes alternating tongues 96 and slots 98 around its circumference. When in the initial position prior to rotation of the guard 90, the tongues 96 are disposed radially outward of and overlapping the barbs 82 of the front housing, to restrain the barbs 82 against radially outward movement. This helps to ensure that the barbs 82 retain the needle assembly 35 in a fixed position by engagement with the collar 37. When the guard 90 is rotated through a given angle, in the illustrated embodiment 60°, as well as bringing the claws 92 into alignment with the axially extending part 88 of the slots in the front housing 80, the slots 98 will be brought into radial alignment with the tongues 82 to permit them to spring outwardly to an extent that allows the collar 37 to be released when the guard 90 is pulled off. As the claws are moved along the linear portion 88 of the slots they will come into engagement with the rear or proximal end 37 of the collar of the needle guard 35 and may therefore pull it away from the needle retainer to allow it to be removed with the guard 90.

An alternative embodiment of the device having a modified front assembly is shown in Figure 26. In this embodiment, the lugs 45 on the cartridge housing 40 have been replaced with grooves 145, one of which is shown in Figure 26. Furthermore, rather than the front housing being provided with inclined tracks 84, the internal surface of the guide sleeve 140 is provided with inwardly projecting lugs (not shown) for engaging the grooves 1 5 on the cartridge housing 40. The combination of the grooves 145 and the cooperating lugs on the inside of the guide sleeve 140 provides the same function as the combination of the lugs 45 and the inclined tracks 84, namely rotation of the cartridge housing 40 during the septum piercing stage (discussed below).

The construction of the front housing and the guard is also different in the embodiment shown in Figure 26. In this alternative embodiment, the guard 190 comprises resilient formations 194 to aid gripping by a user. The formations 194 are provided with circumferentially extending projections 196 on an outer surface thereof. The front housing 180 is provided with corresponding circumferentially extending slots 198 for engaging the projections 196, thus retaining the guard 190 on the front housing 180 prior to use of the device.

In the same manner as guard 90 described above, guard 190 includes claws 92 for engaging the rear surface of the collar 37 on the needle shield 37, such that removal of the guard 190 pulls off the needle shield 35 to expose the needle. In order to remove the guard 190, a user must grip and squeeze the formations 194 so as to deflect them inwardly, thus disengaging the projections 196 from the slots 198. The guard 190 can then be pulled off the device, together with the needle shield 35.

The rear portion of the assembly of the device will now be described by reference to Figure 17 onwards.

Figure 17 corresponds to the view of Figure 16 but showing the assembly of a further component, the needle pusher 100, to the proximal end of the cartridge housing 40.

The needle pusher 100 includes a pair of inwardly extending lugs which are not visible in Figure 17. These lugs engage the proximal end of the slip ring 46 when the device is in its initial condition. The needle pusher 100 is located over the proximal end of the actuating rod 55 and cartridge housing 40, being retained in place by engagement of the inner lugs of the needle pusher 100 with the proximal end of the slip ring 46. This prevents axial movement of the needle pusher 100 relative to the slip ring 46. The needle pusher 100 is rotatable relative to the slip ring 46 and cartridge housing 40. Rotation of the needle pusher 100 may bring the inwardly facing lugs into alignment with the slots 48 and the continuation of the slots 42 in the cartridge housing to permit the needle pusher 100 to slide relative to the cartridge housing 11.

The needle pusher 100 defines a radially outwardly extending lug 108. A similar lug 108 is located on the other side of the needle pusher 100 at 180 degrees to the lug visible in Figure 17.

As shown in Figure 18, an additional cylindrical member, the actuating rod pusher 102 is slid over the proximal end of the actuating rod 55 to be located behind the needle pusher 100. The distal end of the rod pusher 02 engages against the proximal end of the needle pusher 100. The rod pusher 102 includes a pair of radially outwardly extending lugs 106, one of which may be seen in Figure 18. The opposite lug 106 is located at 180 degrees thereto. The proximal end of the rod pusher 102 defines three resilient legs 116 which each terminate in a radially outwardly directed hook 114. The rod pusher 102 includes an L-shaped slot 120 having a linear axial portion 122 which extends distally towards a blind ended circumferentially extending portion 120. This slot may be seen more clearly in Figure 19 which shows the region of the rod pusher 102 in more detail. The rod pusher 102 is mounted over the clutch ring 57 such that the lug 59 of the clutch ring is located initially at the blind end of the circumferential portion 120 of the L-shaped slot. This initial position may be seen more clearly in Figure 20. In this manner, axial movement of the actuating rod pusher 102 will result in movement of the clutch ring 57, and hence the actuating rod pusher by virtue of the engagement of the ring 57 with the teeth of the actuating rod 55. As the clutch ring 57 may not advance relative to the actuating rod 55 when an axial force is applied to the clutch ring 57, the ring 57 will grip the actuating rod to advance the actuating rod with the actuating rod pusher 102.

As will be described in more detail below, as the actuating rod pusher 102 moves axially it is also arranged to rotate relative to the actuating rod and ring 57 by virtue of the engagement of the lug 106 with an inclined track. When the lug 59 of the clutch ring 57 is engaged with the end of the circumferentially extending portion 120 of the L-shaped slot and is at the distal end of the axial linear portion 122, the ring 57 and hence the actuating rod 55 will be free to move rearwardly relative to the actuating rod pusher 102.

Figure 20 shows the assembly of a further component, the spring retainer 110 which is located over the actuating rod 55 proximally of the actuating rod pusher 102. The spring retainer 110 includes a spring-engaging surface 111 which bears against a rear end of a spring when mounted thereto in use. The spring retainer 110 includes connecting fingers 112 for locking the spring retainer 110 in a fixed axial position relative to a guide sleeve 130 of the device as shown in Figure 25.

Figure 21 shows the assembly of Figure 20 with a coil spring 104 assembled thereto. The spring is shown in its initial compressed condition prior to activation of the device, and is located between the spring-engaging surface 111 of the spring retainer 110 and the rear end of the actuating rod pusher 102.

The spring retainer 110 is located distally of the hooks 114 defined by the resilient legs 116 of the actuating rod pusher 102. The hooks 114 hook over the rim defined by the edge of the opening defined in the proximal end of the spring retainer 16 as shown in Figure 24 A. This ensures that the spring is retained in a compressed condition until the hooks 114 unhook from the rim to release the spring. The spring retainer 16 helps to maintain rotational alignment of the actuator rod 55 as it moves into the rear housing 3.

Figure 22 illustrates the assembly of Figure 21 but with a pair of return springs 130 located in the bores 49 of the cartridge housing. The proximal and distal ends of the springs 130 are located against the collar 43 of the cartridge housing 40 and the proximal end 93 of the front housing 80 respectively. The return springs 130 are initially in an uncompressed condition. ln an alternative embodiment shown in Figure 26, a single circular return spring 230 is provided instead of return springs 130. The circular return spring 230 extends about the distal portion of the cartridge 11 , and the proximal end of the spring 203 is located against the collar 43 of the cartridge housing 40. The distal end of the spring 230 engages a movable cup 232. The cup 232 comprises a pair of outwardly extending lugs 234 which are received in axially extending slots 236 provided in the front housing 180. The cup 232 can therefore slide axially along the length of the slots 236.

Before the guard 190 is removed, the hooks 92 provided on the guard 190 engage the cup 232, thus retaining the cup 232 at the proximal end of the slots 236, as shown in Figure 26. In this condition, the spring 230 is compressed.

Upon removal of the guard 190, the spring 230 expands to an uncompressed state, such that the cup slides axially to the distal end of the slots 236. Once in the uncompressed state, the single return spring 230 functions in the same manner as the return springs 130 shown in Figure 22.

Figure 23 is a view similar to Figure 22 but with the spring 104 omitted for clarity and the restoring springs 30 also omitted. The actuating rod pusher 102 is shown cut away to illustrate the position of the clutch ring 57.

Figure 24A illustrates the way in which the retaining legs 116 of the actuating rod pusher 103 are initially hooked over the rear end of the spring retainer 110, and their relationship to the rear housing 3. The guide sleeve 140 is omitted for clarity. Figure 24 B shows the same region of the device but after the spring has been released. The guide sleeve is not shown in Figures 24A and B.

Figure 25 illustrates a guide sleeve 140 which is located over the assembly shown in Figure 22. It may be seen how the retaining fingers 12 of the spring retainer 110 retain the guide sleeve 140 in a fixed position relative thereto. The guide sleeve is keyed to the front housing 80.

The guide sleeve includes a proximal or rear slot 142 and a distal or front slot 144. The rear slot 142 includes proximal or rear portion 130 and a distal or front portion 132. The rear portion is linear. The front portion 132 is inclined. The front or distal slot 144 similarly includes a rear or proximal portion 146 which is linear. The front slot 144 also includes an intermediate portion 148 which is inclined in the opposite direction to the inclined portion 132 of the rear slot. The front slot 144 further includes a front portion 150 which is linear.

Although the linear parts 131 and 146 of the slots 142, 144 are shown as being of different lengths, in practice the distance of travel of the lugs 106, 108 in the linear parts of the slots will be the same, as the lug 106 does not start at the proximal end of the slot 131 as shown in Figure 25. The slot 131 is shown as having a greater axial length than the slot 146 for ease of manufacture. The lug 106 of the actuating rod pusher 102 travels in the rear slot 142 while the lug 108 of the needle pusher 100 travels in the front slot 144. Similar slots of the same configuration as slots 142 and 144 are disposed at 180 degrees on the other side of the guide sleeve for guiding the opposite ones of the pairs of lugs 106, 108.

As shown in Figure 1 , the device further includes a rear housing 3 which is located over the guide sleeve 140. The rear housing extends behind the spring retainer 110 and includes proximal end which is located behind the retaining hooks 114 at the rear end of the legs 116 of the actuating rod pusher 102 as shown in more detail in Figure 24A. Movement of the rear housing 3 distally relative to the front housing 80 will cause the rear end of the rear housing to contact the hooks 114 at the end of the retaining legs 116 of the actuating rod pusher 102. This may urge the legs radially inwardly to enable them to pass through the opening at the centre of the spring retainer 110 to release the spring 104 as shown in Figure 24B.

After the mixing stage is complete, the device is of the appearance of Figure 1 A, but with the actuating rod 55 advanced to be flush with the proximal end of housing 3. The guard 90 is then removed with the needle shield to expose the needle .ready for injection.

Operation of the device will now be described.

The device is initially in the condition shown in Figure 1A. The actuating rod 55 extends from the proximal end of the rear housing 3. The rear or proximal portion 64 of the rod as well as a part of the ratcheted portion 62 are visible. The user initially takes the device in the form shown in Figure 1 A and locates the device vertically with the proximal end of the actuating rod 55 pressed against a horizontal surface. The user then grips the rear housing 3 and urges it downwardly to cause the actuating rod 55 to start to move axially relative to the rear housing 3 into the proximal end of the rear housing 3 and toward the distal end of the device.

Initially the axial movement of housing 3 relative to the actuating rod 55 such that the actuating rod 55 moves relative to the distal end of the device provides a septum piercing stage, causing the distal end of the cartridge to be pushed on to the proximal end of the needle in order to cause the needle 32 to puncture the septum 38 and locate the needle in fluid communication with the interior of the cartridge.

This is achieved because when the user initially pushes down on the rear housing 3, the actuating rod 55 cannot move axially relative to the cartridge housing 40 and hence the cartridge 11. This is because the lugs 50 at the proximal end of the slip ring 48 are not in alignment with the axially extending slots 60 of the actuating rod 55 as shown in Figure 11. The step 75 of the distal end of the actuating rod therefore pushes against the proximal end of the slip ring. Thus over this initial part of the axial movement of the actuating rod relative to the distal end of the device as the housing 3 is moved downwardly, the cartridge 11 is advanced relative to the needle assembly 34. The actuating rod 55 is prevented from rotating by virtue of the cooperation of the lugs 58 of the clutch ring 57 (or single ring 157) which ride in the slots 60 of the actuating rod shown in Figure 8 or 9. This ensures that the rod moves only axially relative to the rear housing 3.

The needle assembly 34, and hence the needle, is located in a fixed axial position by cooperation of the barbs 82 of the front housing 80 with the collar 37 of the needle shield 35 as shown in Figure 1 for example. The barbs 82 engage distally of the collar 37 and grip the collar 37, and are prevented from moving radially outwardly because the guard 90 is in place thereover, and the barbs 82 coincide with the position of the tongues 96 of the guard shown in Figure 16. In this way the needle assembly is initially held in a fixed axial position relative to the distal end of the device during the septum piercing and mixing stages.

As the actuating rod begins to cause the cartridge housing 40 and cartridge 11 to advance relatively axially toward the distal end of the device, the lugs 45 of the cartridge housing ride in the inclined slots 84 of the front housing 80. This causes the cartridge housing 40 to rotate relative to the front housing 80 and actuating rod 55. In some arrangements the inclined slot has a length such that when the lugs 45 reach the end thereof the cartridge 11 , cartridge housing 40 and slip ring 46 will have rotated through an angle of 30 degrees while moving an axial distance of 3 mm toward the distal end of the device. By the time the lugs 45 reach the end of the inclined slots 84, the cartridge housing can move no further in a distal direction relative to the front housing as a result of the engagement between the front stopper 27 of the cartridge and the distal end of the interior of the needle retainer 30. The same process of causing the cartridge housing 40 to rotate can be achieved using the grooves 145 and inwardly extending lugs on the guide sleeve 140, as described above with reference to Figure 26.

By this point the cartridge 11 has been pushed onto the rear end of the needle 32 to perforate the membrane 36 disposed at the proximal end of the needle assembly 34 and cause the rear end of the needle to pass through the septum 38 to locate the needle in fluid communication with the interior of the cartridge 11. Although not shown in the Figures, it is envisaged that a blade or similar may be located between the needle assembly 34 and the distal end of the cartridge to facilitate perforation of the membrane 36, for example including a sharpened projection, rather than relying upon pushing of the blunt end of the cartridge against the paper membrane 36 to rupture it.

It will be appreciated that throughout this initial stage of operation to cause the needle to puncture the septum, there will have been no movement of the pistons 21 , 23 inside the cartridge, and hence the solvent 13 and lyophilized drug 17 remain in separate chambers from one another. The distal end of the actuator rod 55 has not been able to move axially relative to the cartridge.

In accordance with the invention, the septum puncturing stage is completed before there is any mixing of the contents of the two chambers of the cartridge 11. This has the advantage that as soon as mixing occurs, venting of the air 18 in the region distal of the lyophilized drug 17 may occur through the needle.

By the end of the septum piercing stage, the linear movement of the cartridge housing 40 relative to the front housing 80 has meant that the dowel 47 of the cartridge housing 40 has moved into a slot in the inner surface of the front housing 80 to constrain the cartridge housing 40 against rotational movement relative to the front housing 40 during injection delivery after the mixing stage.

The transition between the septum puncturing stage and the mixing of the contents of the chambers of the cartridge is controlled by the rotation of the cartridge housing 40 relative to the front housing 80. Once the lugs 45 of the cartridge housing 40, shown for example in Figure 12, reach the end of the inclined portion 84 of the slot in the front housing, the cartridge housing 40 has rotated through a certain angle defined by the inclination of the inclined portions 84 of the slots.

Referring to Figure 11 , this rotation during the septum piercing stage brings the lugs 50 at the proximal end of the slip ring 46 into alignment with the slots 60 in the actuating rod 55, such that once the rotation of the cartridge housing is complete at the end of the septum piercing stage, the actuating rod to start to slide axially in a distal direction through the slip ring 46 and to advance axially relative to the cartridge housing 40. Thus, as the user continues to push down on the housing, urging the actuating rod 55 further into the housing, the actuating rod no longer pushes the cartridge housing 40 and cartridge 1 forwards towards the front housing, but instead the distal end of the actuating rod 55 starts to enter the cartridge 11 , to advance the piston 21 at the rear of the cartridge 11. This causes the piston 21 and the stopper 24 to slide towards the distal end of the cartridge.

As the solvent 19 located between the stopper 24 and the distal piston 23 is relatively incompressible, this movement of the proximal piston 21 causes the distal piston 23 to also move relatively towards the distal end of the cartridge causing the plug of lyophilized drug 17 to move towards the distal end of the cartridge. The air 18 located initially between the distal end of the plug 17 and the distal end of the cartridge 11 is vented through the needle 32. It is important to try to ensure that all of the air is fully vented from the cartridge before an injection occurs, as it is undesirable for air from the front of the cartridge to enter the bloodstream. In this manner, the piston 23 is moved to a position such that it is in the region of the bypass channel 25, allowing the solvent 19 from the proximal chamber 13 to start to flow through the bypass channel 25 into the front or distal chamber 15 in order to mix with the lyophilized drug 17. In this manner, reconstitution through mixing of the lyophilized drug 17 and solvent 19 starts to occur.

Ultimately the proximal piston 21 moves to a position such that the stopper 24 contacts the proximal end of the piston 23 with the reconstituted liquid drug being located towards the distal or front end of the cartridge 11 distal of the piston 23. By the time the reconstitution stage is complete and the pistons have moved to this position, the distal end of the actuating rod 55 will have moved to be flush with the proximal end of the rear housing 3. The actuating rod 55 may then not be moved further axially relative to the housing 3 by pressing the proximal end of the actuating rod against a surface.

As the actuating rod 55 is pushed into the rear end of the rear housing 3 during the septum piercing and mixing stages, it will be appreciated that the actuating rod will move axially in a stepwise fashion, as the ratchet teeth 70 pass through the ring 57 and diaphragm 74 shown in Figure 10, or the single ring 157 shown in Figure 27. The split diaphragm or the single ring 157 permit the teeth to pass. This ratchet type movement of the actuating rod has been found to be particularly advantageous as it may more effectively cause air to be vented from the front of the cartridge through the needle due to the slight jarring of the actuating rod as it advances.

The drug is now reconstituted providing a liquid ready for injection. Before the device may be used to administer an injection, the user must manually remove the guard 90 or the guard 190 in order to permit initiation of an injection cycle and to release the needle for advancement relative to the distal end of the device.

In order to remove the guard 90, the user must twist the guard 90 through 60 degrees relative to the front housing 80 before pulling it off axially. This rotation causes the claws 92 shown for example in Figure 16 to travel along the circumferential extending part of the slot 86 of the front housing to reach the linear part 88. The rotation of the guard also has the effect that the tongues 96 are moved out of alignment with the underlying barbs 82 which retain the collar 37 of the needle assembly 34. Once the guard 90 has been rotated the barbs 82 are in alignment with the slots 98 allowing the barbs 82 to move radially outwardly slightly. The guard may then be pulled axially off the front of the front housing, with the claws moving along the axial slots 88 and engaging with the collar 37 of the needle shield 35 to pull the needle shield 35 off the needle retainer 30 as the claws move past the collar 37 during their axial movement.

Alternatively, to remove the guard 190, the user must squeeze the formations 194 inwardly and pull the guard 190 off the device, as described above with reference to Figure 26.

The needle is now exposed ready for use, but is located in a retracted position relative to the distal end of the device.

In order to commence an automatic injection cycle, the user must carry out an activation step. This is done by locating the device with the front end of the front housing 80, 180 against the skin of an injection site, and grasping the rear housing 3 and moving it axially towards the distal end of the front housing. This step may only be performed after the guard 90, 190 has been removed to allow movement of the rear housing 3 relative to the front housing 80, 180.

In some arrangements the device may be arranged such that the guard 90, 190 may not be removed until the mixing stage is complete. For example, the device may be located in a secondary packaging which may only be removed when the actuating rod has been depressed by a certain distance.

Referring to Figure 20, and Figures 24 A and B, movement of the outer housing 3 in an axially forward direction toward the distal end of the front housing causes the rear end of the rear housing 3 to ride up the ramped retaining hooks 114 of the actuating rod pusher 102 from the position shown in Figure 24A urging the resilient legs 116 radially inwardly. The hooks 114 therefore unhook from the rim to the rear of the spring retainer 1 0 to release the compressed spring 104. The spring 104 urges forward the actuating rod pusher 102 which in turn pushes forward the needle pusher 100 toward the distal end of the device.

Referring to Figure 25, initially the lug 106 of the actuating rod pusher and the lug 108 of the needle pusher ride in the linear parts 131 and 146 respectively of their slots 142 and 144 in the guide sleeve 140. The actuating rod pusher 102 pushes forward the ring 57, 157 and hence the actuating rod 55, as the ring 57, 157 grips the teeth of the ratchet portion 62.

The slip ring 48 and cartridge housing 40 will have moved forward from their initial position relative to the actuating rod pusher 102 and the needle pusher 100 under the action of the actuating rod during the initial stage to cause puncturing of the septum, as the cartridge is advanced axially in this stage e.g. by around 3 mm. Initially the spring causes the actuating rod pusher 102 to travel forward axially as the lug 106 rides in the linear part 131 of the slot 142, and the needle pusher 100 to move forward as the lug 108 rides in linear slot 146 to come into engagement with the proximal end of slip ring 48. In other words the actuating rod pusher 102 and the needle pusher 100 need to catch up with the slip ring 48 and cartridge housing 40.

Once the parts are engaged with one another, the spring 104 acts on the actuating rod pusher 102 to urge it axially, and the actuating rod pusher 102 in turn acts on the rear end of the needle pusher 100 to move it axially. Initially the inner lugs of the needle retainer 100 are not aligned with the slots 48 in the slip ring 46, and thus the needle pusher pushes forward the slip ring and hence the cartridge housing 40 and cartridge 11. The needle pusher 100 cannot move axially relative to the slip ring 46 or cartridge housing 40. Accordingly the action of the spring forces both the actuating rod pusher 102 and the needle pusher 100 forward axially and hence also moves the slip ring 48, cartridge housing and cartridge forward. The actuating rod pusher 102 engages the ring 57, 157 which grips the teeth 72 of the ratcheted part 62 of the actuating rod 55 to also move the actuating rod forward. Thus the actuating rod, cartridge housing and cartridge all move axially forward to advance the needle into the skin of the user.

Referring to Figure 25, it will be seen that as the actuating rod pusher 102 and needle pusher 100 advance axially so their lugs 106, 108 enter the inclined portions 132 and 148 of the tracks 142 and 144 respectively. Thus the actuating rod pusher 102 and needle pusher 100 start to counter-rotate. Referring to Figure 20, the lug 59 of the ring 57 will start to travel along the circumferentially extending part 120 of the L-shaped slot in the actuating rod pusher as the actuating rod pusher rotates.

As the needle pusher 100 rotates, its inner lugs rotate towards a position in which they are aligned with the axial slots 48, 40 in the cartridge housing. At this point the lug 108 has reached the end of the inclined portion 148 of its slot 144. The needle pusher 100 then starts to move over the cartridge housing effectively decoupling the action of the spring from the cartridge housing. However the actuating rod pusher 102 continues to force the actuating rod 55 axially forward through its engagement with the ring 57, 157 gripping the diaphragm 74. In this way, in the second part of the cycle the distal end of the actuating rod 55 advances into the barrel of the cartridge 11 , forcing the pistons 21 , 23 towards the stopper 27 to eject the liquid from the region in front of the stopper 23 through the needle and into the patient.

It will be appreciated therefore that the device provides distinct needle advancement and dispensing stages, and does not push on the actuating rod during the needle advancement stage. Pushing on the actuating rod only starts to take place when the needle pusher 100 has rotated to bring its inner lugs into alignment with the slots 48, 42 on the cartridge housing.

The spring 104 continues to act on the actuating rod pusher 102 forcing the actuating rod into the rear end of the cartridge until such time as the actuating rod pusher 102 has rotated relative to the lug 59 of the ring 57, 157 to bring the lug 59 to the end of the circumferential portion of the slot 120 to be at the distal end of the axially extending slot 122. At this point the spring force is no longer effective to drive the actuating rod forward as the spring force is no longer transmitted to the ring 57, 157 and hence actuating rod via the actuating rod pusher 102. In the absence of the main force of the spring, the return springs 130, 230 which have been compressed as the cartridge housing 30 was moved forward axially relative to the front housing 80, 80 act to move the cartridge housing rearwardly once more. The cartridge housing moves the slip ring 46 and hence the actuating rod 55 rearwardly. The ring 57, 157 travels rearwardly relative to the actuating rod pusher 102 with the lug 59 riding in the linear part of the slot 122 towards it proximal end to accommodate the retraction. In this way the needle automatically retracts. The needle retracts to a position such that it is proximal to the front or distal end of the front housing 80 thereby shielding the user from any accidental needle stick injuries.

The device may then be disposed of.

The device is a single use disposable device which is prefilled with the necessary components.

The user may look at the window in the outer housing at various stages during operation of the device to check that it is operating correctly. This may enable the user to view the reconstitution stage, checking that the pistons 21 , 23 have moved into engagement with one another and that the plug of lyophilized drug has disappeared, and later the user may check that the reconstituted liquid has been dispensed from the cartridge after the dispensing cycle has been completed. The window in the outer housing must be sufficiently large that the interior of the cartridge may be seen before and after operation of the device. It will be appreciated that during operation of the device the cartridge and its housing will rotate through a given angle e.g. 30 degrees relative to the outer housing as well as moving forward axially by a given distance e.g. 3 mm by the end of the reconstituting stage, and then retracting further after the dispensing stage.

The strength of the main spring may be chosen appropriately. It will be appreciated that lyophilized drugs tend to be used with an aqueous solvent such that the resulting liquid to be dispensed is not highly viscous. Thus it is not always necessary to have a particularly great spring force.

Claims

1. An injection device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use, the device comprising:

a container;

a septum sealing a distal end of the container; and

a needle located distal to the container;

wherein the container comprises a first chamber including a first component and a second chamber including a second component, the first and second chambers being initially separated from one another by a seal to prevent mixing of the first and second components, wherein the device is arranged on activation to provide a septum piercing stage and then a mixing stage;

components for injection;

2. The device of claim 1 , wherein the septum piercing stage comprises a step of mutually compressing the container and the needle in the axial direction to cause the needle to pierce the septum.

3. The device of claim 1 or 2, further comprising a needle retaining arrangement for retaining the needle in a fixed axial position relative to the distal end of the device during the septum piercing stage, and optionally the mixing stage.

4. The device of claim 3, wherein the needle retaining arrangement is arranged to releasably retain the needle in a fixed axial position relative to the distal end of the device, preferably wherein the needle retaining arrangement is arranged such that it may only be released upon manual intervention.

5. The device of claim 4, further comprising a blocking arrangement blocking release of the needle retaining arrangement which must be displaced to release the needle retaining arrangement.

6. The device of any preceding claim, further comprising a guard which must be displaced by a user before delivery of an injection.

7. The device of any preceding claim, further comprising a needle assembly, the needle assembly comprising the needle, a needle holder and a needle shield, and a seal sealing a proximal end of the needle assembly.

8. The device of any preceding claim, wherein the device is arranged such that the seal of the container is displaced axially during the mixing stage to allow the first and second components to mix.

9. The device of claim 8, wherein the container comprises a bypass channel connecting the first and second chambers, the bypass channel being initially blocked by the seal to prevent mixing of the first and second components, wherein displacing the seal axially during the mixing stage unblocks the channel to allow fluid to flow through the channel between the first and second chambers, thus allowing the first and second components to mix.

10. The device of any preceding claim, wherein the transition between the septum piercing stage and the mixing stage is controlled by a change in a rotational position of a rotational part of the device.

11. The device of claim 10, further comprising a container housing within which the container is disposed, and wherein the rotating part is provided by a proximal part of the container housing.

12. The device of claim 10 or 11 , arranged such that the rotating part moves axially relative to a distal end of the device as it rotates during the septum piercing stage, preferably further arranged such that the rotating part cannot move axially during the mixing stage.

13. The device of any preceding claim, wherein the septum piercing and mixing stages occur under the influence of a manual operation by the user.

14. The device of any preceding claim, further comprising an actuator movable axially relative to a distal end of the device, and wherein the rotation of the rotating part occurs as a result of the relative axial movement of the actuator.

15. The device of claim 14, wherein the actuator is arranged to move in a series of discrete steps as it advances axially at least during the mixing stage, and preferably during the septum piercing stage and the mixing stage.

16. The device of claim 5, wherein the actuator comprises a ratcheted portion which cooperates with an engaging arrangement to result in the actuator moving in a series of discrete steps.

17. The device of claim 16, wherein the engaging arrangement comprises a clutch arrangement arranged such that the actuator moves relative to the clutch arrangement in a first direction when a driving force is applied to the actuator and not the clutch arrangement, and such that the actuator will move with the clutch arrangement when a driving force is applied to the clutch arrangement and not the actuator.

18. The device of any of claims 14 to 17, wherein the actuator is arranged such that it cannot rotate as it moves axially relative to the distal end of the device.

19. The device of any of claims 14 to 18, wherein the device is arranged such that the septum piercing stage and the mixing stage occur under the action of the actuator as the actuator moves axially relative to the distal end of the device.

20. The device of any of claims 14 to 19, wherein the device is arranged such that the actuator cannot move axially relative to the container during the septum piercing stage, preferably wherein the rotating part rotates to a second position which permits the actuator to move axially relative to the container during the mixing stage.

21. The device of any of claims 14 to 20, wherein the actuator is arranged to cause a slidable wall at the proximal end of the container to advance within the container in order to breach the seal between the first and second chambers during the mixing stage.

22. The device of any of claims 14 to 21 , further comprising a part having an opening through which a distal end of the actuator must pass in order to cause a proximal slidable wall of the container to advance relative to the distal end of the container, and wherein the distal end of the actuator may only pass through the opening when the part is in a given rotational alignment with the distal end of the actuator, preferably arranged such that rotation of the rotating part brings the distal end of the actuator into the given rotational alignment with the opening to permit the distal end of the actuator to pass therethrough during the mixing stage.

23. The device of any preceding claim, further arranged such that once the septum piercing and mixing stage are complete the device may be used to perform an automatic injection cycle comprising the steps of advancing the needle for insertion, dispensing the composition in the container, and preferably retracting the needle.

24. An injection device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use, the device comprising:

a container;

a septum sealing a distal end of the container; and

a needle located distal to the container;

wherein the container comprises a first chamber including a first component and a second chamber including a second component, the first and second chambers being initially separated from one another by a seal to prevent mixing of the first and second components; wherein the device is arranged on activation to provide a septum piercing stage and then a mixing stage;

components for injection;

wherein the septum piercing stage and the mixing stage occur under the influence of a manual operation by the user, and preferably wherein the device is arranged to automatically perform an injection cycle after the mixing stage comprising the steps of advancing the needle for insertion, dispensing the mixed composition in the container, and preferably retracting the needle.

25. The device of claim 24, further comprising the features of any of claims 1 to 23.

26. The device of any preceding claim, further comprising driving means for driving an actuator forward axiaily to advance a proximal slidable wall of the container within the container for dispensing a mixed composition contained in the container.

27. The device of claim 26, wherein the device is arranged such that during the injection cycle, a driving force is transmitted from the driving means to the actuator during the dispensing stage, and such that a driving force is not transmitted to the actuator during the retraction stage to allow retraction of the needle;

wherein the injection device comprises a drive coupling arrangement between said driving means and the actuator; and

28. An injection device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use, the device comprising:

a container;

an actuator;

a septum sealing a distal end of the container; and

a needle located distal to the container;

components for injection;

wherein the device comprises driving means for driving the actuator forward axially to cause the composition contained in the container to be dispensed;

wherein the device is arranged such that during the injection cycle, a driving force is transmitted from the driving means to the actuator during the dispensing stage, and such that a driving force is not transmitted to the actuator during the retraction stage to allow retraction of the needle;

wherein the injection device comprises a drive coupling arrangement between said driving means and the actuator; and wherein said drive coupling arrangement comprises a drive coupling part selectively transmitting or not transmitting force from the driving means to the actuator depending upon a position of the coupling part, preferably a rotational position thereof.

29. The device of claim 28, further comprising the features of any of claims 1 to 27.

30. The device of claim 27, 28 or 29, wherein the drive coupling arrangement comprises first and second parts which are configurable such that a driving force can be selectively transmitted or not transmitted between them in use depending upon the relative positions of the parts, preferably the relative rotational positions thereof, wherein the first and second parts are arranged such that during operation of the device, a driving force is transmitted between the first and second parts during the dispensing stage for applying a driving force to the actuator, and such that a driving force is not transmitted between the first and second parts during the retraction stage to allow retraction of the needle.

31. The device of claim 30, wherein the second part is arranged to clutch the actuator, whereby the actuator may be advanced relative to the second part in a first direction relative to the distal end of the device when an axial force is applied to the actuator and not the second part during the septum piercing and mixing stages, and wherein the second part cannot move axially relative to the actuator when an axial force is applied to the second part and not the actuator.

32. The device of claim 30 or 31, wherein the first part is arranged to rotate relative to the second part under the action of the driving force transmitted thereto by the driving means in use, the first part being rotatable into a given rotational position relative to the second part in which a driving force is no longer transmitted between the first and second parts in use.

33. The device of claim 32, wherein the second part is arranged to retract relative to the first part when the first part ceases to transmit a driving force thereto in use.

34. The device of any of claims 27 to 33, arranged such that, depending upon a

configuration of the drive coupling arrangement, the container is driven forward during the needle advancement stage, and the actuator is driven forward relative to the container to cause the proximal slidable wall of the container to advance within the container during the dispensing stage for dispensing the composition contained in the container.

35. The device of any of claims 27 to 34, wherein a transition between the needle advancement and dispensing stages is controlled by rotational movement of a part of the drive coupling arrangement.

36. The device of claim 35, wherein the transition is further controlled by simultaneous axial movement of the part of the drive coupling arrangement.

37. An injection device having a proximal end and a distal end, wherein the distal end is located closest to an injection site in use, the device comprising:

an actuator;

a container, wherein the container comprises a first chamber including a first component and a second chamber including a second component, the first and second chambers being initially separated from one another by a seal to prevent mixing of the first and second components;

wherein the device is arranged such that axial movement of the actuator relative to a distal end of the device provides a mixing stage in which the seal between the first and second chambers is breached to allow the first and second components to mix thereby providing a liquid comprising the first and second components for injection; and

38. The device of claim 37, further comprising the features of any of claims 1 to 36.

39. The device of any preceding claim, wherein the first component comprises a liquid, preferably an aqueous liquid.

40. The device of claim 39, wherein the second component comprises a solid or a liquid.

41. A kit of parts for the injection device in accordance with any of claims 1 to 40.

42. An injection device substantially as hereinbefore described with reference to the accompanying drawings.